Systems and methods for vagal nerve stimulation

ABSTRACT

Devices, systems and methods are disclosed for electrical stimulation of the vagus nerve to treat or prevent disorders in a patient. The devices comprise a handheld device having one or more electrode interfaces for contacting the outer skin surface of a patient, a power source and a signal generator coupled to the electrode/interfaces for applying one or more electrical impulses to a deep nerve within the patient, such as the vagus nerve. The device further comprises a filter situated in series between the signal generator and the electrode/interfaces for filtering out undesired high frequency components of the electrical impulses to create a cleaner, smoother signal. The filter may comprise an electrically conductive medium and/or a low-pass filter between the signal generator and the electrode/interface.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation in Part of U.S. Nonprovisionalapplication Ser. No. 13/222,140 filed 31 Aug. 2011; and also is aContinuation in Part of U.S. Nonprovisional application Ser. No.13/222,087 filed 31 Aug. 31, 2011; each of which is incorporated hereinby reference in its entirety.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingconditions associated with stroke and/or transient ischemic attacks. Theenergy impulses (and/or fields) that are used to treat those conditionscomprise electrical and/or electromagnetic energy, deliverednon-invasively to the patient.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes (deep brain stimulation) has been approved for usein the treatment of various conditions, including pain and movementdisorders such as essential tremor and Parkinson's disease [Joel S.PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu. Rev.Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92 (2001):505-513; U.S. Pat. No. 6,871,099,entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to WHITEHURST, et al].

Many other forms of nerve stimulation exist [HATZIS A, Stranjalis G,Megapanos C, Sdrolias P G, Panourias I G, Sakas D E. The current rangeof neuromodulatory devices and related technologies. Acta NeurochirSuppl 97(Pt 1, 2007):21-29]. The type of electrical stimulation that ismost relevant to the present invention is vagus nerve stimulation (VNS,also known as vagal nerve stimulation). It was developed initially forthe treatment of partial onset epilepsy and was subsequently developedfor the treatment of depression and other disorders. The left vagusnerve is ordinarily stimulated at a location within the neck by firstimplanting an electrode about the vagus nerve during open neck surgeryand by then connecting the electrode to an electrical stimulator circuit(a pulse generator). The pulse generator is ordinarily implantedsubcutaneously within a pocket that is created at some distance from theelectrode, which is usually in the left infraclavicular region of thechest. A lead is then tunneled subcutaneously to connect the electrodeassembly and pulse generator. The patient's stimulation protocol is thenprogrammed using a device (a programmer) that communicates with thepulse generator, with the objective of selecting electrical stimulationparameters that best treat the patient's condition (pulse frequency,stimulation amplitude, pulse width, etc.) [U.S. Pat. No. 4,702,254entitled Neurocybernetic prosthesis, to ZABARA; U.S. Pat. No. 6,341,236entitled Vagal nerve stimulation techniques for treatment of epilepticseizures, to OSORIO et al; U.S. Pat. No. 5,299,569 entitled Treatment ofneuropsychiatric disorders by nerve stimulation, to WERNICKE et al; G.C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brainstimulation, vagal nerve stimulation and transcranial stimulation: Anoverview of stimulation parameters and neurotransmitter release.Neuroscience and Biobehavioral Reviews 33 (2009):1042-1060; GROVES D A,Brown V J. Vagal nerve stimulation: a review of its applications andpotential mechanisms that mediate its clinical effects. NeurosciBiobehav Rev 29 (2005):493-500; Reese TERRY, Jr. Vagus nervestimulation: a proven therapy for treatment of epilepsy strives toimprove efficacy and expand applications. Conf Proc IEEE Eng Med BiolSoc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation:current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4; ANDREWS, R.J. Neuromodulation. I. Techniques-deep brain stimulation, vagus nervestimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci.993 (2003):1-13; LABINER, D. M., Ahern, G. L. Vagus nerve stimulationtherapy in depression and epilepsy: therapeutic parameter settings.Acta. Neurol. Scand. 115 (2007):23-33; AMAR, A. P., Levy, M. L., Liu, C.Y., Apuzzo, M. L. J. Vagus nerve stimulation. Proceedings of the IEEE96(7, 2008):1142-1151; CLANCY J A, Deuchars S A, Deuchars J. The wondersof the Wanderer. Exp Physiol 98(1, 2013):38-45].

Prior art vagal nerve stimulators typically have treatment paradigmsthat require continuous stimulation of the vagus nerve. The term“continuous stimulate” as defined herein means stimulation that eitherliterally remains ON for 24 hours/day and seven days/week or follows acertain ON/Off pattern continuously for 24 hours/day and sevendays/week. For example, existing implantable vagal nerve stimulators“continuously stimulate” the vagus nerve with a typical pattern of 30seconds ON/5 minutes OFF (or the like) for 24 hours/day and sevendays/week. Unfortunately, this not only involves a continuous drain onthe power supply of the vagal nerve stimulator, but it makes it verydifficult, if not impossible, to provide treatment with a vagal nervestimulator that is not implanted on the nerve.

SUMMARY OF THE INVENTION

The present invention provides systems, apparatus and methods forselectively applying electrical energy to body tissue, particularly to avagus nerve at a location in a patient's neck. Methods are provided toapply an electrical impulse to modulate, stimulate, inhibit or blockelectrical signals in nerves within or around the carotid sheath, toprevent or treat a condition or symptom of a patient. The electricalsignal may be adapted to reduce, stimulate, inhibit or block electricalsignals in a vagus nerve to treat many conditions, such asbronchoconstriction associated with asthma, COPD or the like,hypotension associated with sepsis or anaphylaxis, allergic rhinitis,chronic sinusitis, stroke, hypertension, diabetes, hypovolemic shock,sepsis, epilepsy, depression, obesity, anxiety disorders, migraine,cluster headache, tension headache, post-concussion headache,post-traumatic stress disorder, GI disorders, autism, stroke, modulationof liver function to alter cholesterol production, neurodegenerativedisorders, such Alzheimer's disease and the like, and any other ailmentaffected by vagus nerve transmissions.

In certain aspects of the invention, a device or system comprises anenergy source of magnetic and/or electrical energy that is transmittedto, or in close proximity to, the vagus nerve to temporarily stimulateand/or modulate the signals in the nerve.

In certain embodiments, the vagal nerve stimulator of the presentinvention is non-invasive. In one preferred embodiment, a method oftreatment includes positioning the coil of a magnetic stimulatornon-invasively on or above a patient's neck and applying amagnetically-induced electrical impulse non-invasively to the targetregion within the neck to stimulate or otherwise modulate selected nervefibers. In another embodiment, surface electrodes are used to applyelectrical impulses non-invasively to the target region within the neckto likewise stimulate or otherwise modulate selected nerve fibers.Preferably, the target region is adjacent to, or in close proximitywith, the carotid sheath that contains a vagus nerve.

In another embodiment of the invention, the stimulator comprises asource of electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve. The stimulator may comprise twoelectrodes that lie side-by-side on the surface of a hand-held enclosureto form an interface between the enclosure and the patient's skin. Theenclosure preferably also includes a power source and a signal generatorcoupled to the electrode interface. However, it should be understoodthat either of these elements (the power source and/or the signalgenerator) may be located exterior to the enclosure and coupled to theelectrodes either directly (e.g., through wires) or wirelessly. A filteris provided within the enclosure to electrically couple theelectrode/interface with the signal generator. The filter is configuredto filter out or eliminate high frequency components of the electricalimpulse or signal generated by the signal generator before thesecomponents reach the electrode.

Filtering the high frequency components from the signal results in asmoother cleaner signal through the electrodes. This filtered signalcauses less discomfort or pain to the patient, particularly at the skinsurface where the signal is being applied. Thus, a sufficiently highamplitude signal may be applied to the patient to cause the electricalimpulse to reach a deeper nerve, such as the vagus nerve, and cause thatnerve to fire an action potential.

In one embodiment, the filter comprises an electrically conductingmedium that extends from the electrode/interface element of thestimulator to the signal generator (or at least the output stage of thesignal generator). The electrically conductive medium may comprisesolution of electrolytes or a conductive gel. Because the conductivemedium is located between the signal generating electronics of thedevice and the electrodes, it acts as a low-pass filter that reduces oreliminates most, if not all, of the undesired high frequency componentsof the signal before the electrical impulse reaches the electrodes.

In another embodiment, the filter comprises a low-pass filterelectrically coupled in series between the signal generator and theelectrode/interface. In this embodiment, the low-pass filter maycomprise a digital or analog filter. In certain embodiments, thelow-pass filter comprises a capacitor.

Current passing through an electrode may be about 0 to about 40 mA, withvoltage across the electrodes of about 0 to about 30 volts. The currentis passed through the electrodes in bursts of pulses. There may be 1 to20 pulses per burst, preferably five pulses. Each pulse within a bursthas a duration of about 20 to about 1000 microseconds, preferably about200 microseconds. A burst followed by a silent inter-burst intervalrepeats at 1 to 5000 bursts per second (bps, similar to Hz), preferablyat 15-50 bps, and even more preferably at 25 bps. The preferred shape ofeach pulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to about 600 V/m(preferably less than about 100 V/m) and an electrical field gradient ofgreater than about 2 V/m/mm. Electric fields that are produced at thevagus nerve are generally sufficient to excite all myelinated A and Bfibers, but not necessarily the unmyelinated C fibers. However, by usinga reduced amplitude of stimulation, excitation of A-delta and B fibersmay also be avoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves in theskin that produce pain.

The novel systems, devices and methods for treating stroke and/ortransient ischemic attacks are more completely described in thefollowing detailed description of the invention, with reference to thedrawings provided herewith, and in claims appended hereto. Otheraspects, features, advantages, etc. will become apparent to one skilledin the art when the description of the invention herein is taken inconjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1A shows structures within a patient's nervous system that may bemodulated by electrical stimulation of a vagus nerve.

FIG. 1B shows functional networks within the brain (resting statenetworks) that may be modulated by electrical stimulation of a vagusnerve.

FIG. 1C shows subcomponents of a resting state network that isresponsible for movements of a stroke patient, as well asinterconnections between those components.

FIG. 1D shows how interconnections between the subcomponents shown inFIG. 1C have changed in the stroke patient, relative to theinterconnections prior to the stroke.

FIG. 2A is a schematic view of an exemplary nerve modulating deviceaccording to the present invention which supplies controlled pulses ofelectrical current to a magnetic stimulator coil.

FIG. 2B is a schematic view of another embodiment of a nerve modulatingdevice according to the present invention which supplies electricalcurrent to surface electrodes.

FIG. 2C illustrates an exemplary electrical voltage/current profileaccording to the present invention.

FIG. 2D illustrates an exemplary waveform for stimulating and/ormodulating impulses that are applied to a nerve.

FIG. 2E illustrates another exemplary waveform for stimulating and/ormodulating impulses applied to a nerve.

FIG. 3A is a perspective view of the top of a dual-toroid magneticstimulator coil according to an embodiment of the present invention.

FIG. 3B is a perspective view of the bottom of the magnetic stimulatorcoil of FIG. 3A.

FIG. 3C is a cut-a-way view of the magnetic stimulator coil of FIG. 3A.

FIG. 3D is another cut-a-way view of the magnetic stimulator coil ofFIG. 3A.

FIG. 3E illustrates the magnetic stimulator coil of FIGS. 3A-3D attachedvia cable to a box containing the device's impulse generator, controlunit, and power source.

FIG. 4A is a perspective view of a dual-electrode stimulator accordingto another embodiment of the present invention.

FIG. 4B is a cut-a-way view of the dual-electrode stimulator of FIG. 4A.

FIG. 4C is an exploded view of one of the electrode assemblies of thedual-electrode stimulator of FIG. 4A.

FIG. 4D is a cut-a-way view of the electrode assembly of FIG. 4C.

FIG. 5A is perspective view of the top of an alternative embodiment ofthe dual-electrode stimulator of FIG. 4A.

FIG. 5B is a perspective view of the bottom of the dual-electrodestimulator of FIG. 5A.

FIG. 5C is a cut-a-way view of the dual-electrode stimulator of FIG. 5A.

FIG. 5D is another cut-a-way view of the dual-electrode stimulator ofFIG. 5.

FIG. 6A illustrates the approximate position of the housing of thestimulator according one embodiment of the present invention, when usedto stimulate the right vagus nerve in the neck of an adult patient.

FIG. 6B illustrates the approximate position for stimulation of a child.

FIG. 7 illustrates the housing of the stimulator according oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 8 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In some embodiments, numbers expressing frequencies, periods of time, orquantities or levels of current, voltage, energy, and so forth, used todescribe and claim certain embodiments of the present disclosure are tobe understood as being modified in some instances by the term “about.”In some embodiments, the term “about” is used to indicate that a valueincludes the standard deviation of the mean for the device or methodbeing employed to determine the value. In some embodiments, thenumerical parameters set forth in the written description and attachedclaims are approximations that can vary depending upon the desiredproperties sought to be obtained by a particular embodiment. In someembodiments, the numerical parameters should be construed in light ofthe number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of some embodiments of thepresent disclosure are approximations, the numerical values set forth inthe specific examples are reported as precisely as practicable. Thenumerical values presented in some embodiments of the present disclosuremay contain certain errors necessarily resulting from the standarddeviation found in their respective testing measurements. The recitationof ranges of values herein is merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range. Unless otherwise indicated herein, each individual value isincorporated into the specification as if it were individually recitedherein.

In one or more embodiments of the present invention, electrical energyis applied in a patient to a target region within or around the carotidsheath (also called the carotid neurovascular bundle) to treat apatient's ailment. The invention is particularly useful for applyingelectrical impulses that ultimately interact with the signals of a vagusnerve, which lies within the carotid sheath, to achieve a therapeuticresult. The nerve stimulation may result in benefits to the patient suchas: relaxation of the smooth muscle of the bronchia for treatment ofbronchoconstriction associated with asthma, COPD and/orexercised-induced bronchoconstriction, increase in blood pressureassociated with orthostatic hypotension, reduction in blood pressure,treatment of epilepsy, treating ileus conditions, depression, anxiety,anaphylaxis, obesity, a neurodegenerative disorder such as Alzheimer'sdisease, migraine, tension-type, cluster, MOH and other types ofheadache, rhinitis, sinusitis, stroke, atrial fibrillation, autism,modulation of liver function, gastroparesis and other functionalgastrointestinal disorders, and/or any other ailment that may beaffected by nerve transmissions of a vagus nerve. Such treatments fordifferent disorders are disclosed in the following US patentapplications assigned to ElectroCore, LLC (the complete disclosures ofwhich are incorporated by reference in their entirety for all purposes):U.S. patent application Ser. No. 13/858,114, filed Apr. 8, 2013(ELEC-47), U.S. patent application Ser. No. 13/783,391, filed Mar. 3,2013 (ELEC-49), U.S. patent application Ser. No. 13/736,096, filed Jan.8, 2013 (ELEC-43), U.S. patent application Ser. No. 13/731,035, filedDec. 30, 2012 (ELEC-46), U.S. patent application Ser. No. 13/603,799filed Sep. 5, 2012 (ELEC-44-1), U.S. patent application Ser. No.13/357,010, filed Jan. 24, 2012 (ELEC-41), U.S. patent application Ser.No. 13/279,437 filed Oct. 24, 2011 (ELEC-40), U.S. patent applicationSer. No. 13/222,087 filed Aug. 31, 2011 (ELEC-39), U.S. patentapplication Ser. No. 13/183,765 filed Jul. 15, 2011 (ELEC-38), U.S.patent application Ser. No. 13/183,721 filed Jul. 15, 2011, now U.S.Pat. No. 8,676,330 issued Mar. 18, 2014 (ELEC-36), U.S. patentapplication Ser. No. 13/109,250 filed May 17, 2011, now U.S. Pat. No.8,676,324 issued Mar. 18, 2014 (ELEC-37), U.S. patent application Ser.No. 13/075,746 filed Mar. 30, 2011 (ELEC-35), U.S. patent applicationSer. No. 13/024,727, filed Feb. 10, 2011 (ELEC-34), U.S. patentapplication Ser. No. 13/005,005 filed Jan. 12, 2011 (ELEC-33), U.S.patent application Ser. No. 12/964,050 filed Dec. 9, 2010 (ELEC-32),U.S. patent application Ser. No. 12/859,568 filed Aug. 9, 2010(ELEC-31), U.S. patent application Ser. No. 12/408,131 filed Mar. 20,2009 (ELEC-17CP1) and U.S. patent application Ser. No. 12/612,177 filedNov. 9, 2009 now U.S. Pat. No. 8,041,428 issued Oct. 18, 2011(ELEC-14CP1).

The fact that electrical stimulation of a vagus nerve can be used totreat so many disorders may be understood as follows. The vagus nerve iscomposed of motor and sensory fibers. The vagus nerve leaves thecranium, passes down the neck within the carotid sheath to the root ofthe neck, then passes to the chest and abdomen, where it contributes tothe innervation of the viscera. A human vagus nerve (tenth cranialnerve, paired left and right) consists of over 100,000 nerve fibers(axons), mostly organized into groups. The groups are contained withinfascicles of varying sizes, which branch and converge along the nerve.Under normal physiological conditions, each fiber conducts electricalimpulses only in one direction, which is defined to be the orthodromicdirection, and which is opposite the antidromic direction. However,external electrical stimulation of the nerve may produce actionpotentials that propagate in orthodromic and antidromic directions.Besides efferent output fibers that convey signals to the various organsin the body from the central nervous system, the vagus nerve conveyssensory (afferent) information about the state of the body's organs backto the central nervous system. Some 80-90% of the nerve fibers in thevagus nerve are afferent (sensory) nerves, communicating the state ofthe viscera to the central nervous system.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths.

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia, which take the form of swellingsnear the base of the skull. Vagal afferents traverse the brainstem inthe solitary tract, with some eighty percent of the terminating synapsesbeing located in the nucleus of the tractus solitarius (or nucleustractus solitarii, nucleus tractus solitarius, or NTS). The NTS projectsto a wide variety of structures in the central nervous system, such asthe amygdala, raphe nuclei, periaqueductal gray, nucleusparagigantocellurlais, olfactory tubercule, locus ceruleus, nucleusambiguus and the hypothalamus. The NTS also projects to the parabrachialnucleus, which in turn projects to the hypothalamus, the thalamus, theamygdala, the anterior insula, and infralimbic cortex, lateralprefrontal cortex, and other cortical regions [JEAN A. The nucleustractus solitarius: neuroanatomic, neurochemical and functional aspects.Arch Int Physiol Biochim Biophys 99(5, 1991):A3-A52]. Thus, stimulationof vagal afferents can modulate the activity of many structures of thebrain and brainstem through these projections.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections controls parasympathetic function primarilybelow the level of the diaphragm, while the ventral vagal complex,comprised of nucleus ambiguus and nucleus retrofacial, controlsfunctions primarily above the diaphragm in organs such as the heart,thymus and lungs, as well as other glands and tissues of the neck andupper chest, and specialized muscles such as those of the esophagealcomplex. For example, the cell bodies for the preganglionicparasympathetic vagal neurons that innervate the heart reside in thenucleus ambiguus, which is relevant to potential cardiovascular sideeffects that may be produced by vagus nerve stimulation.

The vagus efferent fibers innervate parasympathetic ganglionic neuronsthat are located in or adjacent to each target organ. The vagalparasympathetic tone resulting from the activity of these fibers isbalanced reflexly in part by sympathetic innervations. Consequently,electrical stimulation of a vagus nerve may result not only inmodulation of parasympathetic activity in postganglionic nerve fibers,but also a reflex modulation of sympathetic activity. The ability of avagus nerve to bring about widespread changes in autonomic activity,either directly through modulation of vagal efferent nerves, orindirectly via activation of brainstem and brain functions that arebrought about by electrical stimulation of vagal afferent nerves,accounts for the fact that vagus nerve stimulation can treat manydifferent medical conditions in many end organs. Selective treatment ofparticular conditions is possible because the parameters of theelectrical stimulation (frequency, amplitude, pulse width, etc.) mayselectively activate or modulate the activity of particular afferent orefferent A, B, and/or C fibers that result in a particular physiologicalresponse in each individual.

As ordinarily practiced, the electrodes used to stimulate a vagus nerveare implanted about the nerve during open neck surgery. For manypatients, this may be done with the objective of implanting permanentelectrodes to treat epilepsy, depression, or other conditions [Arun PaulAMAR, Michael L. Levy, Charles Y. Liu and Michael L. J. Apuzzo. Chapter50. Vagus nerve stimulation. pp. 625-638, particularly 634-635. In:Elliot S. Krames, P. Hunber Peckham, Ali R. Rezai, eds. Neuromodulation.London: Academic Press, 2009; KIRSE D J, Werle A H, Murphy J V, Eyen TP, Bruegger D E, Hornig G W, Torkelson R D. Vagus nerve stimulatorimplantation in children. Arch Otolaryngol Head Neck Surg 128(11,2002):1263-1268]. In that case, the electrode is often a spiralelectrode, although other designs may be used as well [U.S. Pat. No.4,979,511, entitled Strain relief tether for implantable electrode, toTERRY, Jr.; U.S. Pat. No. 5,095,905, entitled Implantable neuralelectrode, to KLEPINSKI]. In other patients, a vagus nerve iselectrically stimulated during open-neck thyroid surgery in order toconfirm that the nerve has not been accidentally damaged during thesurgery. In that case, a vagus nerve in the neck is surgically exposed,and a temporary stimulation electrode is clipped about the nerve[SCHNEIDER R, Randolph G W, Sekulla C, Phelan E, Thanh P N, Bucher M,Machens A, Dralle H, Lorenz K. Continuous intraoperative vagus nervestimulation for identification of imminent recurrent laryngeal nerveinjury. Head Neck. 2012 Nov. 20. doi: 10.1002/hed.23187 (Epub ahead ofprint, pp. 1-8)].

It is also possible to electrically stimulate a vagus nerve using aminimally invasive surgical approach, namely percutaneous nervestimulation. In that procedure, a pair of electrodes (an active and areturn electrode) are introduced through the skin of a patient's neck tothe vicinity of a vagus nerve, and wires connected to the electrodesextend out of the patient's skin to a pulse generator [Publicationnumber US20100241188, entitled Percutaneous electrical treatment oftissue, to J. P. ERRICO et al.; SEPULVEDA P, Bohill G, Hoffmann T J.Treatment of asthmatic bronchoconstriction by percutaneous low voltagevagal nerve stimulation: case report. Internet J Asthma Allergy Immunol7 (2009):e1 (pp 1-6); MINER, J. R., Lewis, L. M., Mosnaim, G. S., Varon,J., Theodoro, D. Hoffman, T. J. Feasibility of percutaneous vagus nervestimulation for the treatment of acute asthma exacerbations. Acad EmergMed 2012; 19: 421-429], the complete disclosures of which areincorporated herein by reference in their entirety for all purposes.

Percutaneous nerve stimulation procedures had previously been describedprimarily for the treatment of pain, but not for a vagus nerve, which isordinarily not considered to produce pain and which presents specialchallenges [HUNTOON M A, Hoelzer B C, Burgher A H, Hurdle M F, Huntoon EA. Feasibility of ultrasound-guided percutaneous placement of peripheralnerve stimulation electrodes and anchoring during simulated movement:part two, upper extremity. Reg Anesth Pain Med 33(6, 2008):558-565; CHANI, Brown A R, Park K, Winfree C J. Ultrasound-guided, percutaneousperipheral nerve stimulation: technical note. Neurosurgery 67(3 SupplOperative, 2010):ons136-139; MONTI E. Peripheral nerve stimulation: apercutaneous minimally invasive approach. Neuromodulation 7(3,2004):193-196; Konstantin V SLAVIN. Peripheral nerve stimulation forneuropathic pain. US Neurology 7(2, 2011):144-148].

In one embodiment, the stimulation device is introduced through apercutaneous penetration in the patient to a target location within,adjacent to, or in close proximity with, the carotid sheath thatcontains the vagus nerve. Once in position, electrical impulses areapplied through the electrodes of the stimulation device to one or moreselected nerves (e.g., vagus nerve or one of its branches) to stimulate,block or otherwise modulate the nerve(s) and treat the patient'scondition or a symptom of that condition. For some conditions, thetreatment may be acute, meaning that the electrical impulse immediatelybegins to interact with one or more nerves to produce a response in thepatient. In some cases, the electrical impulse will produce a responsein the nerve(s) to improve the patient's condition or symptom in lessthan 3 hours, preferably less than 1 hour and more preferably less than15 minutes. For other conditions, intermittently scheduled or as-neededstimulation of the nerve may produce improvements in the patient overthe course of several days, weeks, months or years. A more completedescription of a suitable percutaneous procedure for vagal nervestimulation can be found in commonly assigned, co-pending US patentapplication titled “Percutaneous Electrical Treatment of Tissue”, filedApr. 13, 2009 (Ser. No. 12/422,483), the complete disclosure of which ishereby incorporated by reference in its entirety for all purposes.

In another embodiment of the invention, a time-varying magnetic field,originating and confined to the outside of a patient, generates anelectromagnetic field and/or induces eddy currents within tissue of thepatient. In another embodiment, electrodes applied to the skin of thepatient generate currents within the tissue of the patient. An objectiveof the invention is to produce and apply the electrical impulses so asto interact with the signals of one or more nerves, in order to preventor avert a stroke and/or transient ischemic attack, to ameliorate orlimit the effects of an acute stroke or transient ischemic attack,and/or to rehabilitate a stroke patient.

Much of the disclosure will be directed specifically to treatment of apatient by electromagnetic stimulation in or around a vagus nerve, withdevices positioned non-invasively on or near a patient's neck. However,it will also be appreciated that the devices and methods of the presentinvention can be applied to other tissues and nerves of the body,including but not limited to other parasympathetic nerves, sympatheticnerves, spinal or cranial nerves. As recognized by those having skill inthe art, the methods should be carefully evaluated prior to use inpatients known to have preexisting cardiac issues. In addition, it willbe recognized that the treatment paradigms of the present invention canbe used with a variety of different vagal nerve stimulators, includingimplantable and/or percutaneous stimulation devices, such as the onesdescribed above.

FIG. 1A shows the location of the stimulation as “Vagus NerveStimulation,” relative to its connections with other anatomicalstructures that are potentially affected by the stimulation. Indifferent embodiments of the invention, various brain and brainstemstructures are preferentially modulated by the stimulation. Thesestructures will be described in sections of the disclosure that follow,along with the rationale for modulating their activity as a prophylaxisor treatment for stroke or transient ischemic attack. As a preliminarymatter, we first describe the vagus nerve itself and its most proximalconnections, which are particularly relevant to the disclosure below ofthe electrical waveforms that are used to perform the stimulation.

The vagus nerve (tenth cranial nerve, paired left and right) is composedof motor and sensory fibers. The vagus nerve leaves the cranium, passesdown the neck within the carotid sheath to the root of the neck, thenpasses to the chest and abdomen, where it contributes to the innervationof the viscera.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves, communicating the state of the viscera to thecentral nervous system. Propagation of electrical signals in efferentand afferent directions are indicated by arrows in FIG. 1A. Ifcommunication between structures is bidirectional, this is shown in FIG.1A as a single connection with two arrows, rather than showing theefferent and afferent nerve fibers separately.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths. It is understood that the anatomy ofthe vagus nerve is developing in newborns and infants, which accounts inpart for the maturation of autonomic reflexes. Accordingly, it is alsounderstood that the parameters of vagus nerve stimulation in the presentinvention are chosen in such a way as to account for this age-relatedmaturation [PEREYRA P M, Zhang W, Schmidt M, Becker L E. Development ofmyelinated and unmyelinated fibers of human vagus nerve during the firstyear of life. J Neurol Sci 110(1-2, 1992):107-113; SCHECHTMAN V L,Harper R M, Kluge K A. Development of heart rate variation over thefirst 6 months of life in normal infants. Pediatr Res 26(4,1989):343-346].

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia. These ganglia take the form ofswellings found in the cervical aspect of the vagus nerve just caudal tothe skull. There are two such ganglia, termed the inferior and superiorvagal ganglia. They are also called the nodose and jugular ganglia,respectively (See FIG. 1A). The jugular (superior) ganglion is a smallganglion on the vagus nerve just as it passes through the jugularforamen at the base of the skull. The nodose (inferior) ganglion is aganglion on the vagus nerve located in the height of the transverseprocess of the first cervical vertebra.

Vagal afferents traverse the brainstem in the solitary tract, with someeighty percent of the terminating synapses being located in the nucleusof the tractus solitarius (or nucleus tractus solitarii, nucleus tractussolitarius, or NTS, see FIG. 1A). The NTS projects to a wide variety ofstructures in the central nervous system, such as the amygdala, raphenuclei, periaqueductal gray, nucleus paragigantocellurlais, olfactorytubercule, locus ceruleus, nucleus ambiguus and the hypothalamus. TheNTS also projects to the parabrachial nucleus, which in turn projects tothe hypothalamus, the thalamus, the amygdala, the anterior insula, andinfralimbic cortex, lateral prefrontal cortex, and other corticalregions [JEAN A. The nucleus tractus solitarius: neuroanatomic,neurochemical and functional aspects. Arch Int Physiol Biochim Biophys99(5, 1991):A3-A52]. Such central projections are discussed below inconnection with the interoception and resting state neural networks.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections (see FIG. 1A), controls parasympatheticfunction primarily below the level of the diaphragm (e.g. gut and itsenterochromaffin cells), while the ventral vagal complex, comprised ofnucleus ambiguus and nucleus retrofacial, controls functions primarilyabove the diaphragm in organs such as the heart, thymus and lungs, aswell as other glands and tissues of the neck and upper chest, andspecialized muscles such as those of the esophageal complex. Forexample, the cell bodies for the preganglionic parasympathetic vagalneurons that innervate the heart reside in the nucleus ambiguus, whichis relevant to potential cardiovascular side effects that may beproduced by vagus nerve stimulation.

With the foregoing as preliminary information about the vagus nerve, thetopics that are presented below in connection with the disclosure of theinvention include the following: (1) Overview of physiologicalmechanisms through which the disclosed vagus nerve stimulation methodsmay be used to modulate the neuronal circuitry of individuals at riskfor, or who have experienced, a stroke and/or transient ischemic attack;(2) Description of Applicant's magnetic and electrode-based nervestimulating devices, describing in particular the electrical waveformused to stimulate a vagus nerve; (3) Preferred embodiments of themagnetic stimulator; (4) Preferred embodiments of the electrode-basedstimulator; (5) Application of the stimulators to the neck of thepatient; (6) Use of the devices with feedback and feedforward to improvetreatment of individual patients.

Overview of physiological mechanisms through which the disclosed vagusnerve stimulation methods may be used to modulate the neuronal circuitryof individuals individuals at risk for, or who have suffered, a strokeand/or transient ischemic attack.

We now disclose methods and devices for electrically stimulating a vagusnerve noninvasively, in order to provide medical treatment to anindividual at risk for, or who has suffered, a stroke and/or transientischemic attack. The disclosed methods and devices are an extension ofmethods and devices that have been developed for the treatment of otherconditions, as follows. Non-invasive stimulation of the cervical vagusnerve (nVNS) is a novel technology for treating various central nervoussystem disorders, primarily by stimulating specific afferent fibers ofthe vagus nerve to modulate brain function. This technology has beendemonstrated in animal and human studies to treat a wide range ofcentral nervous system disorders including headache (chronic and acutecluster and migraine), epilepsy, bronchoconstriction, anxiety disorders,depression, rhinitis, fibromyalgia, irritable bowel syndrome, stroke,traumatic brain injury, PTSD, Alzheimer's disease, autism, and others.Applicants have discovered that a two-minute stimulation has effectsthat may last up to 8 hours or longer depending on the type and severityof indication.

Broadly speaking, applicant has determined that there are threecomponents to the effects of nVNS on the brain. The strongest effectoccurs during the two minute stimulation and results in significantchanges in brain function that can be clearly seen as acute changes inautonomic function (e.g. measured using pupillometry, heart ratevariability, galvanic skin response, or evoked potential) and activationand inhibition of various brain regions as shown in fMRI imagingstudies. The second effect, of moderate intensity, lasts for 15 to 180minutes after stimulation. Animal studies have shown changes inneurotransmitter levels in various parts of the brain that persist forseveral hours. The third effect, of mild intensity, lasts up to 8 hoursand is responsible for the long lasting alleviation of symptoms seenclinically and, for example, in animal models of migraine headache.

Thus, depending on the medical indication, whether it is a chronic oracute treatment, and the natural history of the disease, differenttreatment protocols may be used. In particular, applicant has discoveredthat it is not necessary to “continuously stimulate” the vagus nerve (orto in order to provide clinically efficacious benefits to patients withcertain disorders. The term “continuously stimulate” as defined hereinmeans stimulation that follows a certain On/Off pattern continuously 24hours/day. For example, existing implantable vagal nerve stimulators“continuously stimulate” the vagus nerve with a pattern of 30 secondsON/5 minutes OFF (or the like) for 24 hours/day and seven days/week.Applicant has determined that this continuous stimulation is notnecessary to provide the desired clinical benefit for many disorders.For example, in the treatment of acute migraine attacks, the treatmentparadigm may comprise two minutes of stimulation at the onset of pain,followed by another two minute stimulation 15 minutes later. Forepilepsy, three 2 minute stimulations three times per day appear to beoptimal. Sometimes, multiple consecutive, two minute stimulations arerequired. Thus, the initial treatment protocol corresponds to what maybe optimum for the population of patients at large for a givencondition. However, the treatment may then be modified on anindividualized basis, depending on the response of each particularpatient.

The present invention contemplates three types of interventionsinvolving stimulation of a vagus nerve: prophylactic, acute andcompensatory (rehabilitative). Among these, the acute treatment involvesthe fewest administrations of vagus nerve stimulations, which begin uponthe appearance of symptoms. It is intended primarily to enlist andengage the autonomic nervous system to inhibit excitatoryneurotransmissions that accompany the symptoms. The prophylactictreatment resembles the acute treatment in the sense that it isadministered as though acute symptoms had just occurred (even thoughthey have not) and is repeated at regular intervals, as though thesymptoms were reoccurring (even though they are not). The rehabilitativeor compensatory treatments, on the other hand, seek to promote long-termadjustments in the central nervous system, compensating for deficienciesthat arose as the result of the patient's disease by making new neuralcircuits.

A vagus nerve stimulation treatment according to the present inventionis conducted for continuous period of thirty seconds to five minutes,preferably about 90 seconds to about three minutes and more preferablyabout two minutes (each defined as a single dose). After a dose has beencompleted, the therapy is stopped for a period of time (depending on thetreatment as described below). For prophylactic treatments, such as atreatment to avert a stroke or transient ischemic attack, the therapypreferably comprises multiple doses/day over a period of time that maylast from one week to a number of years. In certain embodiments, thetreatment will comprise multiple doses at predetermined times during theday and/or at predetermined intervals throughout the day. In exemplaryembodiments, the treatment comprises one of the following: (1) 3doses/day at predetermined intervals or times; (2) two doses, eitherconsecutively, or separated by 5 min at predetermined intervals ortimes, preferably two or three times/day; (3) 3 doses, eitherconsecutively or separated by 5 min again at predetermined intervals ortimes, such as 2 or 3 times/day; or (4) 1-3 doses, either consecutivelyor separated by 5 min, 4-6 times per day. Initiation of a treatment maybegin when an imminent stroke or TIA is forecasted, or in a risk-factorreduction program it may be performed throughout the day beginning afterthe patient arises in the morning.

In an exemplary embodiment, each treatment session comprises 1-3 dosesadministered to the patient either consecutively or separated by 5minutes. The treatment sessions are administered every 15, 30, 60 or 120minutes during the day such that the patient could receive 2 doses everyhour throughout a 24 hour day.

For certain disorders, the time of day can be more important than thetime interval between treatments. For example, the locus correleus hasperiods of time during a 24 hour day wherein it has inactive periods andactive periods. Typically, the inactive periods can occur in the lateafternoon or in the middle of the night when the patient is asleep. Itis during the inactive periods that the levels of inhibitioryneurotransmitters in the brain that are generated by the locus correleusare reduced. This may have an impact on certain disorders. For example,patients suffering from migraines or cluster headaches often receivethese headaches after an inactive period of the locus correleus. Forthese types of disorders, the prophylactic treatment is optimal duringthe inactive periods such that the amounts of inhibitoryneurotransmitters in the brain can remain at a higher enough level tomitigate or abort an acute attack of the disorder.

In these embodiments, the prophlatic treatment may comprise multipledoses/day timed for periods of inactivity of the locus correleus. In oneembodiment, a treatment according to the present invention comprises oneor more doses administered 2-3 times per day or 2-3 “treatment sessions”per day. The treatment sessions preferably occur during the lateafternoon or late evening, in the middle of the night and again in themorning when the patient wakes up. In an exemplary embodiment, eachtreatment session comprises 1-4 doses, preferably 2-3 doses, with eachdose lasting for about 90 seconds to about three minutes.

For other disorders, the intervals between treatment sessions may be themost important as applicant has determined that stimulation of the vagusnerve can have a prolonged effect on the inhibitor neurotransmitterslevels in the brain, e.g., at least one hour, up to 3 hours andsometimes up to 8 hours. In one embodiment, a treatment according to thepresent invention comprises one or more doses (i.e., treatment sessions)administered at intervals during a 24 hour period. In a preferredembodiment, there are 1-5 such treatment sessions, preferably 2-4treatment sessions. Each treatment session preferably comprises 1-3doses, each lasting between about 60 seconds to about three minutes,preferably about 90 seconds to about 150 seconds, more preferably about2 minutes.

For an acute treatment, such as treatment of acute stroke, the therapyaccording to the present invention may comprise one or more embodiments:(1) 1 dose at the onset of symptoms; (2) 1 dose at the onset ofsymptoms, followed by another dose at 5-15 min; or (3) 1 dose every 15minutes to 1 hour at the onset of symptoms until the acute attack hasbeen mitigated or aborted. In these embodiments, each dose preferablylast between about 60 seconds to about three minutes, preferably about90 seconds to about 150 seconds, more preferably about 2 minutes.

For long term treatment of an acute insult such as one that occursduring the rehabilitation of a stroke patient, the therapy may consistof: (1) 3 treatments/day; (2) 2 treatments, either consecutively orseparated by 5 min, 3×/day; (3) 3 treatments, either consecutively orseparated by 5 min, 2×/day; (4) 2 or 3 treatments, either consecutivelyor separated by 5 min, up to 10×/day; or (5) 1, 2 or 3 treatments,either consecutively or separated by 5 min, every 15, 30, 60 or 120 min.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or migraine thatoccur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

The prophylactic treatments may be most effective when the patient is ina prodromal, high-risk bistable state. In that state, the patient issimultaneously able to remain normal or exhibit symptoms, and theselection between normal and symptomatic states depends on theamplification of fluctuations by physiological feedback networks. Forexample, a thrombus may exist in either a gel or fluid phase, with thefeedback amplification of fluctuations driving the change of phaseand/or the volume of the gel phase. Thus, a thrombus may form or not,depending on the nonlinear dynamics exhibited by the network of enzymesinvolved in clot formation, as influenced by blood flow and inflammationthat may be modulated by vagus nerve stimulation [PANTELEEV M A,Balandina A N, Lipets E N, Ovanesov M V, Ataullakhanov F I.Task-oriented modular decomposition of biological networks: triggermechanism in blood coagulation. Biophys J 98(9, 2010):1751-1761; AlexeyM SHIBEKO, Ekaterina S Lobanova, Mikhail A Panteleev and Fazoil IAtaullakhanov. Blood flow controls coagulation onset via the positivefeedback of factor VII activation by factor Xa. BMC Syst Biol 2010; 4(2010):5, pp. 1-12]. Consequently, the mechanisms of vagus nervestimulation treatment during prophylaxis for a stroke are generallydifferent than what occurs during an acute treatment, when thestimulation inhibits excitatory neurotransmission that follows the onsetof ischemia that is already caused by the thrombus. Nevertheless, theprophylactic treatment may also inhibit excitatory neurotransmission soas to limit the excitation that would eventually occur upon formation ofa thrombus, and the acute treatment may prevent the formation of anotherthrombus.

The circuits involved in such inhibition are illustrated in FIG. 1A.Excitatory nerves within the dorsal vagal complex generally useglutamate as their neurotransmitter. To inhibit neurotransmission withinthe dorsal vagal complex, the present invention makes use of thebidirectional connections that the nucleus of the solitary tract (NTS)has with structures that produce inhibitory neurotransmitters, or itmakes use of connections that the NTS has with the hypothalamus, whichin turn projects to structures that produce inhibitoryneurotransmitters. The inhibition is produced as the result of thestimulation waveforms that are described below. Thus, acting inopposition to glutamate-mediated activation by the NTS of the areapostrema and dorsal motor nucleus are: GABA, and/or serotonin, and/ornorepinephrine from the periaqueductal gray, raphe nucei, and locuscoeruleus, respectively. FIG. 1A shows how those excitatory andinhibitory influences combine to modulate the output of the dorsal motornucleus. Similar influences combine within the NTS itself, and thecombined inhibitory influences on the NTS and dorsal motor nucleusproduce a general inhibitory effect.

The activation of inhibitory circuits in the periaqueductal gray, raphenucei, and locus coeruleus by the hypothalamus or NTS may also causecircuits connecting each of these structures to modulate one another.Thus, the periaqueductal gray communicates with the raphe nuclei andwith the locus coeruleus, and the locus coeruleus communicates with theraphe nuclei, as shown in FIG. 1A [PUDOVKINA O L, Cremers T I, WesterinkB H. The interaction between the locus coeruleus and dorsal raphenucleus studied with dual-probe microdialysis. Eur J Pharmacol 7 (2002);445(1-2):37-42.; REICHLING D B, Basbaum A I. Collateralization ofperiaqueductal gray neurons to forebrain or diencephalon and to themedullary nucleus raphe magnus in the rat. Neuroscience 42(1,1991):183-200; BEHBEHANI M M. The role of acetylcholine in the functionof the nucleus raphe magnus and in the interaction of this nucleus withthe periaqueductal gray. Brain Res 252(2, 1982):299-307]. Theperiaqueductal gray, raphe nucei, and locus coeruleus also project tomany other sites within the brain, including those that would be excitedduring ischemia. Therefore, in this aspect of the invention, vagus nervestimulation during acute stroke or transient ischemic attack has ageneral neuroprotective, inhibitory effect via its activation of theperiaqueductal gray, raphe nucei, and locus coeruleus.

In particular, the vagus nerve stimulation may be neuroprotective to apart of the brain known as the insula (also known as the insularycortex, insular cortex, or insular lobe) and its connections with theanterior cingulate cortex (ACC). Neural circuits leading from the vagusnerve to the insula and ACC are shown in FIG. 1A. Protection of theinsula is particularly important for stroke patients, because damage tothe insula is known to cause symptoms that are typical in strokepatients, involving motor control, hand and eye motor movement, motorlearning, swallowing, speech articulation, the capacity for long andcomplex spoken sentences, sensation, and autonomic functions [ANDERSON TJ, Jenkins I H, Brooks D J, Hawken M B, Frackowiak R S, Kennard C.Cortical control of saccades and fixation in man. A PET study. Brain117(5, 1994):1073-1084; FINK G R, Frackowiak R S, Pietrzyk U, PassinghamR E (April 1997). Multiple nonprimary motor areas in the human cortex.J. Neurophysiol 77 (4, 1997): 2164-2174; SOROS P, Inamoto Y, Martin R E.Functional brain imaging of swallowing: an activation likelihoodestimation meta-analysis. Hum Brain Mapp 30(8, 2009):2426-2439; DRONKERSN F. A new brain region for coordinating speech articulation. Nature 384(6605, 1996): 159-161; ACKERMANN H, Riecker A. The contribution of theinsula to motor aspects of speech production: a review and a hypothesis.Brain Lang 89 (2, 2004): 320-328; BOROVSKY A, Saygin A P, Bates E,Dronkers N. Lesion correlates of conversational speech productiondeficits. Neuropsychologia 45 (11, 2007): 2525-2533; OPPENHEIMER S M,Kedem G, Martin W M. Left-insular cortex lesions perturb cardiacautonomic tone in humans. Clin Auton Res; 6(3, 1996):131-140; CRITCHLEYH D. Neural mechanisms of autonomic, affective, and cognitiveintegration. J. Comp. Neurol. 493 (1, 2005): 154-166].

FIG. 1C illustrates one example of the present invention for treating apatient suffereing from stroke, illustrating exemplary connectionsbetween components of the SMN. Components shown there are: cerebellum(Cereb), primary motor cortex (M1), prefrontal cortex (PFC), lateralpremotor cortex (PMC), supplementary motor area (SMA), superior parietalcortex (SPC) and thalamus (Thal). As also shown there, the componentsare paired within the brain, and the components in the left half of thefigure represent the ones in the brain hemisphere that are affected bythe stroke. FIG. 1D shows increases and decreases in excitatory andinhibitory interactions among these components, relative to connectionsin the SMN prior to the stroke. As in FIG. 1C, components in the lefthalf of the figure are the ones in the brain hemisphere that areaffected by the stroke [REHME A K, Grefkes C. Cerebral network disordersafter stroke: evidence from imaging-based connectivity analyses ofactive and resting brain states in humans. J Physiol 591(Pt 1,2013):17-31; INMAN C S, James G A, Hamann S, Rajendra J K, Pagnoni G,Butler A J. Altered resting-state effective connectivity offronto-parietal motor control systems on the primary motor networkfollowing stroke. Neuroimage 59(1, 2012):227-237].

It is understood that additional SMA components are involved inspecialized muscle movements. For example, the components most involvedin the loss and recovery of speech following a stroke are thesupplementary motor area (SMA, see FIGS. 1C and 1D) and its interactionwith the right Broca-homologue (not shown) [SAUR D, Lange R,Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, Weiller C.Dynamics of language reorganization after stroke. Brain 129(2006):1371-1384].

Description of Preferred Embodiments of Magnetic and Electrode-BasedNerve Stimulating/Modulating Devices

Devices of the invention that are used to stimulate a vagus nerve willnow be described. Either a magnetic stimulation device or anelectrode-based device may be used for that purpose. FIG. 2A is aschematic diagram of Applicant's magnetic nerve stimulating/modulatingdevice 301 for delivering impulses of energy to nerves for the treatmentof medical conditions. As shown, device 301 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and a magnetic stimulator coil 341coupled via wires to impulse generator coil 310. The stimulator coil 341is toroidal in shape, due to its winding around a toroid of corematerial.

Although the magnetic stimulator coil 341 is shown in FIG. 2A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 2Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed below, coil 341 actuallycontains two coils that may be connected either in series or in parallelto the impulse generator 310.

The item labeled in FIG. 2A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below, the conducting medium with which thecoil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is also adapted hereinfor use with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient, at the siteof stimulation on the skin, than stimulator devices that are currentlyknown in the art. Conversely, for a given amount of pain or discomforton the part of the patient (e.g., the threshold at which such discomfortor pain begins), the design achieves a greater depth of penetration ofthe stimulus under the skin.

An alternate embodiment of the present invention is shown in FIG. 2B,which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 2B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 2Brepresent all electrodes of the device collectively.

The item labeled in FIG. 2B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with particular embodiments of theinvention, conducting medium in which the electrode 340 is embedded neednot completely surround an electrode. As also described below inconnection with a preferred embodiment, the volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, contain descriptionsof pulse generators that may be applicable to the present invention. Byway of example, a pulse generator is also commercially available, suchas Agilent 33522A Function/Arbitrary Waveform Generator, AgilentTechnologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard, computer mouse, andtouchscreen, as well as any externally supplied physiological signals(see FIG. 8), analog-to-digital converters for digitizing externallysupplied analog signals (see FIG. 8), communication devices for thetransmission and receipt of data to and from external devices such asprinters and modems that comprise part of the system, hardware forgenerating the display of information on monitors that comprise part ofthe system, and busses to interconnect the above-mentioned components.Thus, the user may operate the system by typing instructions for thecontrol unit 330 at a device such as a keyboard and view the results ona device such as the system's computer monitor, or direct the results toa printer, modem, and/or storage disk. Control of the system may bebased upon feedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmur

o, Przemys

aw P

onecki, Jacek Starzyński, Stanis

aw Wincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 2C illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the coil 341 or electrodes 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator programming toimprove treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produce an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated, as well as the outputs of various sensors which senseprevailing conditions prevailing in this substance, whereby the user ofthe system can manually adjust the signal, or have it automaticallyadjusted by feedback, to provide an electrical stimulation signal ofwhatever type the user wishes, who can then observe the effect of thissignal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to about 100 Hz, preferably between about 15-50 Hz and morepreferably between about 15-35 Hz. In an exemplary embodiment, thefrequency is about 25 Hz. The modulation signal may have a pulse widthselected to influence the therapeutic result, such as about 1microseconds to about 1000 microseconds, preferably about 100-400microseconds and more preferably about 200-400 microseconds. Forexample, the electric field induced or produced by the device withintissue in the vicinity of a nerve may be about 5 to about 600 V/m,preferably less than about 100 V/m, and even more preferably less thanabout 30 V/m. The gradient of the electric field may be greater thanabout 2 V/m/mm. More generally, the stimulation device produces anelectric field in the vicinity of the nerve that is sufficient to causethe nerve to depolarize and reach a threshold for action potentialpropagation, which is about 8 V/m at 1000 Hz. The modulation signal mayhave a peak voltage amplitude selected to influence the therapeuticresult, such as about 0.2 volts or greater, such as about 0.2 volts toabout 40 volts, preferably between about 1-20 volts and more preferablybetween about 2-12 volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inU.S. Pat. No. 6,234,953, entitled Electrotherapy device using lowfrequency magnetic pulses, to THOMAS et al. and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al. One mayalso vary stimulation parameters iteratively, in search of an optimalsetting [U.S. Pat. No. 7,869,885, entitled Threshold optimization fortissue stimulation therapy, to BEGNAUD et al]. However, some stimulationwaveforms, such as those described herein, are discovered by trial anderror, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J. Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering 51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulation ofPeripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2D and 2E. As seen there, individual sinusoidal pulses have aperiod of □, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period □ may be between about 50-1000microseconds (equivalent to about 1-20 KHz), preferably between about100-400 microseconds (equivalent to about 2.5-10 KHz), more preferablyabout 133-400 microseconds (equivalent to about 2.5-7.5 KHZ) and evenmore preferably about 200 microseconds (equivalent to about 5 KHz); thenumber of pulses per burst may be N=1-20, preferably about 2-10 and morepreferably about 5; and the whole pattern of burst followed by silentinter-burst period may have a period T comparable to about 10-100 Hz,preferably about 15-50 Hz, more preferably about 25-35 Hz and even morepreferably about 25 Hz (a much smaller value of T is shown in FIG. 2E tomake the bursts discernable). When these exemplary values are used for Tand □, the waveform contains significant Fourier components at higherfrequencies ( 1/200 microseconds=5000/sec), as compared with thosecontained in transcutaneous nerve stimulation waveforms, as currentlypracticed.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters □, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med 10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation: The Early Experiments. Physical Therapy 82 (10, 2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. Burst stimulation has also been disclosed in connectionwith implantable pulse generators, but wherein the bursting ischaracteristic of the neuronal firing pattern itself [U.S. Pat. No.7,734,340 to D E RIDDER, entitled Stimulation design forneuromodulation; application US20110184486 to D E RIDDER, entitledCombination of tonic and burst stimulations to treat neurologicaldisorders]. By way of example, the electric field shown in FIGS. 2D and2E may have an E_(max) value of 17 V/m, which is sufficient to stimulatethe nerve but is significantly lower than the threshold needed tostimulate surrounding muscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011].

Those methods involve high-frequency modulation in the range of fromabout 1.5 KHz to about 50 KHz, which is applied to the patient's spinalcord region. However, such methods are different from the presentinvention because, for example, they is invasive; they do not involve abursting waveform, as in the present invention; they necessarily involveA-delta and C nerve fibers and the pain that those fibers produce,whereas the present invention does not; they may involve a conductionblock applied at the dorsal root level, whereas the present inventionmay stimulate action potentials without blocking of such actionpotentials; and/or they involve an increased ability of high frequencymodulation to penetrate through the cerebral spinal fluid, which is notrelevant to the present invention. In fact, a likely explanation for thereduced back pain that is produced by their use of frequencies from 10to 50 KHz is that the applied electrical stimulus at those frequenciescauses permanent damage to the pain-causing nerves, whereas the presentinvention involves only reversible effects [LEE R C, Zhang D, Hannig J.Biophysical injury mechanisms in electrical shock trauma. Annu RevBiomed Eng 2 (2000):477-509].

Consider now which nerve fibers may be stimulated by the non-invasivevagus nerve stimulation. The waveform disclosed in FIG. 2 containssignificant Fourier components at high frequencies (e.g., 1/200microseconds=5000/sec), even if the waveform also has components atlower frequencies (e.g., 25/sec). Transcutaneously, A-beta, A-delta, andC fibers are typically excited at 2000 Hz, 250 Hz, and 5 Hz,respectively, i.e., the 2000 Hz stimulus is described as being specificfor measuring the response of A-beta fibers, the 250 Hz for A-deltafibers, and the 5 Hz for type C fibers [George D. BAQUIS et al.TECHNOLOGY REVIEW: THE NEUROMETER CURRENT PERCEPTION THRESHOLD (CPT).Muscle Nerve 22(Supplement 8, 1999): S247-S259]. Therefore, the highfrequency component of the noninvasive stimulation waveform willpreferentially stimulate the A-alpha and A-beta fibers, and the C fiberswill be largely unstimulated.

However, the threshold for activation of fiber types also depends on theamplitude of the stimulation, and for a given stimulation frequency, thethreshold increases as the fiber size decreases. The threshold forgenerating an action potential in nerve fibers that are impaled withelectrodes is traditionally described by Lapicque or Weiss equations,which describe how together the width and amplitude of stimulus pulsesdetermine the threshold, along with parameters that characterize thefiber (the chronaxy and rheobase). For nerve fibers that are stimulatedby electric fields that are applied externally to the fiber, as is thecase here, characterizing the threshold as a function of pulse amplitudeand frequency is more complicated, which ordinarily involves thenumerical solution of model differential equations or a case-by-caseexperimental evaluation [David BOINAGROV, Jim Loudin and DanielPalanker. Strength-Duration Relationship for Extracellular NeuralStimulation: Numerical and Analytical Models. J Neurophysiol 104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins APL Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 μm diameter fiber, 12.3 V/m for a 10 μm fiber, and 24.6V/m for a 5 μm diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to 100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 toabout 100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS M S, Verma-Ahuja S, Naritoku D K, Espinosa J A.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110 (2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the largest A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282 (1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in the side-effect ofbronchoconstriction, evidently the bronchoconstrictive B-fibers arepossibly not being activated when the amplitude is properly set. Also,the absence of bradycardia or prolongation of PR interval suggests thatcardiac efferent B-fibers are not stimulated. Similarly, A-deltaafferents may behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

To summarize the foregoing discussion, the delivery of an impulse ofenergy sufficient to stimulate and/or modulate transmission of signalsof vagus nerve fibers will result in the inhibition of excitatoryneurotramsmitters and to a more normal activity within higher centers ofthe brain, many of which are components of resting state networks. Themost likely mechanisms do not involve the stimulation of C fibers; andthe stimulation of afferent nerve fibers activates neural pathwayscauses the release of norepinephrine, and/or serotonin and/or GABA.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 8). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

Preferred Embodiments of the Magnetic Stimulator

A preferred embodiment of magnetic stimulator coil 341 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999, (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Although Carbunaru and Durand demonstrated that it is possible toelectrically stimulate a patient transcutaneously with such a device,they made no attempt to develop the device in such a way as to generallyshape the electric field that is to stimulate the nerve. In particular,the electric fields that may be produced by their device are limited tothose that are radially symmetric at any given depth of stimulation intothe patient (i.e, two variables, z and rho, are used to specify locationof the field, not x, y, and z). This is a significant limitation, and itresults in a deficiency that was noted in FIG. 6 of their publication:“at large depths of stimulation, the threshold current [in the device'scoil] for long axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein.

Accordingly, it is an objective of the present invention to shape anelongated electric field of effect that can be oriented parallel to sucha long nerve. The term “shape an electric field” as used herein means tocreate an electric field or its gradient that is generally not radiallysymmetric at a given depth of stimulation in the patient, especially afield that is characterized as being elongated or finger-like, andespecially also a field in which the magnitude of the field in somedirection may exhibit more than one spatial maximum (i.e. may be bimodalor multimodal) such that the tissue between the maxima may contain anarea across which induced current flow is restricted. Shaping of theelectric field refers both to the circumscribing of regions within whichthere is a significant electric field and to configuring the directionsof the electric field within those regions. The shaping of the electricfield is described in terms of the corresponding field equations incommonly assigned application US20110125203 (application Ser. No.12/964,050), entitled Magnetic stimulation devices and methods oftherapy, to SIMON et al., which is hereby incorporated by reference.

Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Whereas the toroid inthe CARBUNARU and Durand publication was immersed in a homogeneousconducting half-space, this is not necessarily the case for ourinvention. Although our invention will generally have some continuouslyconducting path between the device's coil and the patient's skin, theconducting medium need not totally immerse the coil, and there may beinsulating voids within the conducting medium. For example, if thedevice contains two toroids, conducting material may connect each of thetoroids individually to the patient's skin, but there may be aninsulating gap (from air or some other insulator) between the surfacesat which conducting material connected to the individual toroids contactthe patient. Furthermore, the area of the conducting material thatcontacts the skin may be made variable, by using an aperture adjustingmechanism such as an iris diaphragm. As another example, if the coil iswound around core material that is laminated, with the core in contactwith the device's electrically conducting material, then the laminationmay be extended into the conducting material in such a way as to directthe induced electrical current between the laminations and towards thesurface of the patient's skin. As another example, the conductingmaterial may pass through apertures in an insulated mesh beforecontacting the patient's skin, creating thereby an array of electricfield maxima.

In the dissertation cited above, Carbunaru-FAIERSTEIN made no attempt touse conducting material other than agar in a KCl solution, and he madeno attempt to devise a device that could be conveniently and safelyapplied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity of the conductingmaterial and select boundary conditions, thereby shaping the electricfields and currents as described above, but also to create devices thatcan be applied practically to any surface of the body. The volume of thecontainer containing electrically conducting medium is labeled in FIG.2A as 351. Use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 percentto about 0.1 percent of the current conventionally applied to a magneticstimulation coil. This allows for minimal heating of the coil(s) anddeeper tissue stimulation. However, application of the conducting mediumto the surface of the patient is difficult to perform in practicebecause the tissue contours (head, arms, legs, neck, etc.) are notplanar. To solve this problem, in the preferred embodiment of thepresent invention, the toroidal coil is embedded in a structure which isfilled with a conducting medium having approximately the sameconductivity as muscle tissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCl solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J. Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13 pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 341 in FIG. 2Areduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain other peripheralnerves.

This preferred embodiment of the magnetic stimulation device is shown inFIG. 3. FIGS. 3A and 3B respectively provide top and bottom views of theouter surface of the toroidal magnetic stimulator 30. FIGS. 3C and 3Drespectively provide top and bottom views of the toroidal magneticstimulator 30, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 3A-3D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 3B-3D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 2A). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 3C and 3D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (4, 2001):434-441].

FIGS. 3C and 3D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 3D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

Signal generators for magnetic stimulators have been described forcommercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 OHR, United Kingdom, 2006], as well as for customdesigns for a control unit 330, impulse generator 310 and power source320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu.Magnetic Stimulation of Neural Tissue: Techniques and System Design. pp293-352, In: Implantable Neural Prostheses 1, Devices and Applications,D. Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.7,744,523, entitled Drive circuit for magnetic stimulation, to CharlesM. Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magneticstimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPoison]. Conventional magnetic nerve stimulators use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil, and which therebyproduces a magnetic pulse. Typically, a transformer charges a capacitorin the impulse generator 310, which also contains circuit elements thatlimit the effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit 330, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY R K, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology 85 (1992): 253-264;Nafia AL-MUTAWALY, Hubert de Bruin, and Gary Hasey. The effects of pulseconfiguration on magnetic stimulation. Journal of ClinicalNeurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless required to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be required, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.].

Commercially available magnetic stimulators include circular, parabolic,figure-of-eight (butterfly), and custom designs that are availablecommercially [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 OHR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 341 have been described [U.S. Pat. No.6,179,770, entitled Coil assemblies for magnetic stimulators, to StephenMould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design. IEEETransactions on Biomedical Engineering, Vol. 47 (No. 11, November 2000):1493-1499]. Many of the problems that are associated with suchconventional magnetic stimulators, e.g., the complexity of theimpulse-generator circuitry and the problem with overheating, arelargely avoided by the toroidal design shown in FIG. 3.

Thus, use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 percentto about 0.1 percent of the current conventionally applied to a magneticstimulation coil. Therefore, with the present invention, it is possibleto generate waveforms shown in FIG. 2 with relatively simple, low-powercircuits that are powered by batteries. The circuits may be enclosedwithin a box 38 as shown in FIG. 3E, or the circuits may be attached tothe stimulator itself (FIG. 3A-3D) to be used as a hand-held device. Ineither case, control over the unit may be made using only an on/offswitch and power knob. The only other component that may be needed mightbe a cover 39 to keep the conducting fluid from leaking or drying outbetween uses. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described inconnection with FIGS. 2D and 2E, shaping an elongated electrical fieldof effect.

Preferred Embodiments of the Electrode-Based Stimulator

In another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil. The vagus nervehas been stimulated previously non-invasively using electrodes appliedvia leads to the surface of the skin. It has also been stimulatednon-electrically through the use of mechanical vibration [HUSTON J M,Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M et al(2007). Transcutaneous vagus nerve stimulation reduces serum highmobility group box 1 levels and improves survival in murine sepsis. CritCare Med 35: 2762-2768; GEORGE M S, Aston-Jones G. Noninvasivetechniques for probing neurocircuitry and treating illness: vagus nervestimulation (VNS), transcranial magnetic stimulation (TMS) andtranscranial direct current stimulation (tDCS). Neuropsychopharmacology35(1, 2010):301-316]. However, no such reported uses of noninvasivevagus nerve stimulation were directed to the treatment of stroke ortransient ischemic attack patients. U.S. Pat. No. 7,340,299, entitledMethods of indirectly stimulating the vagus nerve to achieve controlledasystole, to John D. PUSKAS, discloses the stimulation of the vagusnerve using electrodes placed on the neck of the patient, but thatpatent is unrelated to the treatment of stroke or transient ischemicattacks. Non-invasive electrical stimulation of the vagus nerve has alsobeen described in Japanese patent application JP2009233024A with afiling date of Mar. 26, 2008, entitled Vagus Nerve Stimulation System,to Fukui YOSHIHOTO, in which a body surface electrode is applied to theneck to stimulate the vagus nerve electrically. However, thatapplication pertains to the control of heart rate and is unrelated tothe treatment of stroke or transient ischemic attacks. In patentpublication US20080208266, entitled System and method for treatingnausea and vomiting by vagus nerve stimulation, to LESSER et al.,electrodes are used to stimulate the vagus nerve in the neck to reducenausea and vomiting, but this too is unrelated to the treatment ofstroke or transient ischemic attacks.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimilator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. U.S. Pat. No. 4,865,048,entitled Method and apparatus for drug free neurostimulation, toECKERSON, teaches electrical stimulation of a branch of the vagus nervebehind the ear on the mastoid processes, in order to treat symptoms ofdrug withdrawal. KRAUS et al described similar methods of stimulation atthe ear [KRAUS T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C(2007). BOLD fMRI deactivation of limbic and temporal brain structuresand mood enhancing effect by transcutaneous vagus nerve stimulation. JNeural Transm 114: 1485-1493]. However, none of the disclosures in thesepatents or patent applications for electrical stimulation of the vagusnerve at the ear are used to treat stroke or transient ischemic attacks.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

Considering that the nerve stimulating device 301 in FIG. 2A and thenerve stimulating device 302 in FIG. 2B both control the shape ofelectrical impulses, their functions are analogous, except that onestimulates nerves via a pulse of a magnetic field, and the otherstimulates nerves via an electrical pulse applied through surfaceelectrodes. Accordingly, general features recited for the nervestimulating device 301 apply as well to the latter stimulating device302 and will not be repeated here. The preferred parameters for eachnerve stimulating device are those that produce the desired therapeuticeffects.

A preferred embodiment of an electrode-based stimulator is shown in FIG.4A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 4B. As shown, the stimulator (730) comprises two heads(731) and a body (732) that joins them. Each head (731) contains astimulating electrode. The body of the stimulator (732) contains theelectronic components and battery (not shown) that are used to generatethe signals that drive the electrodes, which are located behind theinsulating board (733) that is shown in FIG. 4B. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (731) using wires. Furthermore, otherembodiments of the invention may contain a single such head or more thantwo heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes or collars, or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when power is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and power source) are compact, portable, and simple to operate.

Details of one embodiment of the stimulator head are shown in FIGS. 4Cand 4D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 2B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 4D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 2B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B.

The head-cup (744) is filled with conducting material (350 in FIG. 2B),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield N.J. 07004. The head-cup (744) and body of thestimulator are made of a non-conducting material, such as acrylonitrilebutadiene styrene. The depth of the head-cup from its top surface to theelectrode may be between one and six centimeters. The head-cup may havea different curvature than what is shown in FIG. 4, or it may be tubularor conical or have some other inner surface geomety that will affect theNeumann boundary conditions that determine the electric field strength.

In certain embodiments, the disc interface 743 actually functions as theelectrode and the screw 745 is simply the output connection to thesignal generator electronics. In this embodiment, electricallyconductive fluid or gel is positioned between the signal generator andthe interface or electrode 745. In this embodiment, the conductive fluidfilters out or eliminates high frequency components from the signal tosmooth out the signal before it reaches the electrode(s) 745. When thesignal is generated, power switching and electrical noise typically addunwanted high frequency spikes back into the signal. In addition, thepulsing of the sinusoidal bursts may induce high frequency components inthe signal. By filtering the signal just before it reaches theelectrodes 745 with the conductive fluid, a smoother, cleaner signal isapplied to the patient, thereby reducing the pain and discomfort felt bythe patient and allowing a higher amplitude to be applied to thepatient. This allows a sufficiently strong signal to be applied to reacha deeper nerve, such as the vagus nerve, without causing too much painand discomfort to the patient at the surface of their skin.

In other embodiments, a low-pass filter may be used instead of theelectrically conductive fluid to filter out the undesirable highfrequency components of the signal. The low-pass filter may comprise adigital or analog filter or simply a capacitor placed in series betweenthe signal generator and the electrode/interface.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 4C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 2B. Thus, anembodiment without the membrane is shown in FIGS. 4C and 4D. Thisversion of the device comprises a solid (but possibly flexible in someembodiments) conducting disc that cannot absorb fluid, thenon-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 4D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out. In addition, this feature allows the user toeasily clean the outer surface of the device (e.g., with isopropylalcohol or similar disinfectant), avoiding potential contaminationduring subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface (351 inFIG. 2B) is made from a very thin material with a high dielectricconstant, such as material used to make capacitors. For example, it maybe Mylar having a submicron thickness (preferably in the range about 0.5to about 1.5 microns) having a dielectric constant of about 3. Becauseone side of Mylar is slick, and the other side is microscopically rough,the present invention contemplates two different configurations: one inwhich the slick side is oriented towards the patient's skin, and theother in which the rough side is so-oriented. Thus, at stimulationFourier frequencies of several kilohertz or greater, the dielectricinterface will capacitively couple the signal through itself, because itwill have an impedance comparable to that of the skin. Thus, thedielectric interface will isolate the stimulator's electrode from thetissue, yet allow current to pass. In one embodiment of the presentinvention, non-invasive electrical stimulation of a nerve isaccomplished essentially substantially capacitively, which reduces theamount of ohmic stimulation, thereby reducing the sensation the patientfeels on the tissue surface. This would correspond to a situation, forexample, in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to about 5 microns (preferably about 1 micron) with adielectric constant of about 3. For a piezoelectric material like bariumtitanate or PZT (lead zirconate titanate), the thickness could be about100-400 microns (preferably about 200 microns or about 0.2 mm) becausethe dielectric constant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2). In addition, the capacitive electrode allows for the use of aninterface that provides a more adequate seal of the interior of thedevice. The capacitive electrode may be used by applying a small amountof conductive material (e.g., conductive gel as described above) to itsouter surface. In some embodiments, it may also be used by contactingdry skin, thereby avoiding the inconvenience of applying an electrodegel, paste, or other electrolytic material to the patient's skin andavoiding the problems associated with the drying of electrode pastes andgels. Such a dry electrode would be particularly suitable for use with apatient who exhibits dermatitis after the electrode gel is placed incontact with the skin [Ralph J. COSKEY. Contact dermatitis caused by ECGelectrode jelly. Arch Dermatol 113 (1977): 839-840]. The capacitiveelectrode may also be used to contact skin that has been wetted (e.g.,with tap water or a more conventional electrolyte material) to make theelectrode-skin contact (here the dielectric constant) more uniform [A LALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect ofcomposition on the dielectric properties of hydrogels for biomedicalapplications. Physiol. Meas. 31 (2010) S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25 (1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2, 2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. U.S. Pat. No. 7,904,180,entitled Capacitive medical electrode, to JUOLA et al, describes acapacitive electrode that includes transcutaneous nerve stimulation asone intended application, but that patent does not describe stimulationvoltages or stimulation waveforms and frequencies that are to be usedfor the transcutaneous stimulation. U.S. Pat. No. 7,715,921, entitledElectrodes for applying an electric field in-vivo over an extendedperiod of time, to PALTI, and U.S. Pat. No. 7,805,201, entitled Treatinga tumor or the like with an electric field, to PALTI, also describecapacitive stimulation electrodes, but they are intended for thetreatment of tumors, do not disclose uses involving nerves, and teachstimulation frequencies in the range of 50 kHz to about 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25 (1987): 359-360; Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 5,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 2B) is the conducting material itself. FIGS. 5A and 5Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 2B), and thepower-level controller is attached to the control unit (330 in FIG. 2B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 2B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.2B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 2B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 5 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.2B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, the stimulator's conducting materials may be nonmagnetic,and the stimulator may be connected to the impulse generator by longnonmagnetic wires (345 in FIG. 2B), so that the stimulator may be usedin the vicinity of a strong magnetic field, possibly with added magneticshielding. As another example, there may be more than two electrodes;the electrodes may comprise multiple concentric rings; and theelectrodes may be disc-shaped or have a non-planar geometry. They may bemade of other metals or resistive materials such as silicon-rubberimpregnated with carbon that have different conductive properties[Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu.Rev. Biomed. Eng. 2008. 10:275-309; Michael F. NOLAN. Conductivedifferences in electrodes used with transcutaneous electrical nervestimulation devices. Physical Therapy 71 (1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 4 and 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 4and 5 provide a uniform surface current density, which would otherwisebe a potential advantage of electrode arrays, and which is a trait thatis not shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jørgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21 (1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71 (1999): 4944-4950].In fact, patients found the design shown in FIGS. 4 and 5 to be lesspainful in a direct comparison with a commercially availablegrid-pattern electrode [UltraStim grid-pattern electrode, AxelggardManufacturing Company, 520 Industrial Way, Fallbrook Calif., 2011]. Theembodiment of the electrode that uses capacitive coupling isparticularly suited to the generation of uniform stimulation currents[Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of currentdensity under stimulating electrodes. Critical Reviews in BiomedicalEngineering 17(1990, 6): 585-619].

The electrode-based stimulator designs shown in FIGS. 4 and 5 situatethe electrode remotely from the surface of the skin within a chamber,with conducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; U.S. Pat.No. 3,590,810, entitled Biomedical body electode, to Kopecky; U.S. Pat.No. 3,279,468, entitled Electrotherapeutic facial mask apparatus, to LeVine; U.S. Pat. No. 6,757,556, entitled Electrode sensor, to Gopinathanet al; U.S. Pat. No. 4,383,529, entitled Iontophoretic electrode device,method and gel insert, to Webster; U.S. Pat. No. 4,220,159, entitledElectrode, to Francis et al. U.S. Pat. No. 3,862,633, U.S. Pat. No.4,182,346, and U.S. Pat. No. 3,973,557, entitled Electrode, to Allisonet al; U.S. Pat. No. 4,215,696, entitled Biomedical electrode withpressurized skin contact, to Bremer et al; and U.S. Pat. No. 4,166,457,entitled Fluid self-sealing bioelectrode, to Jacobsen et al.] Thestimulator designs shown in FIGS. 4 and 5 are also self-contained units,housing the electrodes, signal electronics, and power supply. Portablestimulators are also known in the art, for example, U.S. Pat. No.7,171,266, entitled Electroacupuncture device with stimulation electrodeassembly, to Gruzdowich. One of the novelties of the designs shown inFIGS. 4 and 5 is that the stimulator, along with a correspondinglysuitable stimulation waveform, shapes the electric field, producing aselective physiological response by stimulating that nerve, but avoidingsubstantial stimulation of nerves and tissue other than the targetnerve, particularly avoiding the stimulation of nerves that producepain. The shaping of the electric field is described in terms of thecorresponding field equations in commonly assigned applicationUS20110230938 (application Ser. No. 13/075,746) entitled Devices andmethods for non-invasive electrical stimulation and their use for vagalnerve stimulation on the neck of a patient, to SIMON et al., which ishereby incorporated by reference.

In one embodiment, the magnetic stimulator coil 341 in FIG. 2A has abody that is similar to the electrode-based stimulator shown in FIG. 5C.To compare the electrode-based stimulator with the magnetic stimulator,refer to FIG. 5D, which shows the magnetic stimulator 530 sectionedalong its long axis to reveal its inner structure. As described below,it reduces the volume of conducting material that must surround atoroidal coil, by using two toroids, side-by-side, and passingelectrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 2A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 2A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 2A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4, 2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 2A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Application of the Stimulators to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3, 4 and 5 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 50 or 530 in FIG. 5 is shown to be applied to thetarget location on the patient's neck as described above. For reference,FIG. 6A shows the locations of the following vertebrae: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77. FIG. 6B shows the stimulator50 applied to the neck of a child, which is partially immobilized with afoam cervical collar 78 that is similar to ones used for neck injuriesand neck pain. The collar is tightened with a strap 79, and thestimulator is inserted through a hole in the collar to reach the child'sneck surface. As shown, the stimulator is turned on and off with aswitch that is located on the stimulator, and the amplitude ofstimulation may be adjusted with a control knob that is also located onthe stimulator. In other models, the stimulator may be turned on and offremotely, using a wireless controller that may be used to adjust all ofthe stimulation parameters of the controller (on/off, stimulationamplitude, frequency, etc.).

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6. As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 7, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 7, with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7, using the electrical stimulation devicesthat are disclosed herein. Stimulation may be performed on the left orright vagus nerve or on both of them simulataneously or alternately. Theposition and angular orientation of the device are adjusted about thatlocation until the patient perceives stimulation when current is passedthrough the stimulator electrodes. The applied current is increasedgradually, first to a level wherein the patient feels sensation from thestimulation. The power is then increased, but is set to a level that isless than one at which the patient first indicates any discomfort.Straps, harnesses, or frames are used to maintain the stimulator inposition. The stimulator signal may have a frequency and otherparameters that are selected to produce a therapeutic result in thepatient. Stimulation parameters for each patient are adjusted on anindividualized basis. Ordinarily, the amplitude of the stimulationsignal is set to the maximum that is comfortable for the patient, andthen the other stimulation parameters are adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period tau may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 10 to about 1000 microseconds (i.e., about 1 toabout 10 KHz), preferably about 200 microseconds (about 5 KHz). A burstfollowed by a silent inter-burst interval repeats at 1 to 5000 burstsper second (bps), preferably at 5-50 bps, and even more preferably 10-25bps stimulation (10-25 Hz). The preferred shape of each pulse is a fullsinusoidal wave, although triangular or other shapes may be used aswell.

A vagus nerve stimulation treatment according to the present inventionis conducted for continuous period of thirty seconds to five minutes,preferably about 90 seconds to about three minutes and more preferablyabout two minutes (each defined as a single dose). After a dose has beencompleted, the therapy is stopped for a period of time (depending on thetreatment as described below). For prophylactic treatments, such as atreatment to reduce or eliminate the severity, duration and/or number ofmigraines suffered by a patient, the therapy preferably comprisesmultiple doses/day over a period of time that may last from one week toa number of years. In certain embodiments, the treatment will comprisemultiple doses at predetermined times during the day and/or atpredetermined intervals throughout the day. In exemplary embodiments,the treatment comprises one of the following: (1) 3 doses/day atpredetermined intervals or times; (2) two doses, either consecutively,or separated by 5 min at predetermined intervals or times, preferablytwo or three times/day; (3) 3 doses, either consecutively or separatedby 5 min again at predetermined intervals or times, such as 2 or 3times/day; or (4) 1-3 doses, either consecutively or separated by 5 min,4-6 times per day. Initiation of a treatment may begin when an imminentattack (e.g., headache, seizure, etc) is forecasted, or in a risk-factorreduction program it may be performed throughout the day beginning afterthe patient arises in the morning.

For certain disorders, the time of day can be more important than thetime interval between treatments. For example, the locus correleus hasperiods of time during a 24 hour day wherein it has inactive periods andactive periods. Typically, the inactive periods can occur in the lateafternoon or in the middle of the night when the patient is asleep. Itis during the inactive periods that the levels of inhibitioryneurotransmitters in the brain that are generated by the locus correleusare reduced. This may have an impact on certain disorders. For example,patients suffering from migraines or cluster headaches often receivethese headaches after an inactive period of the locus correleus. Forthese types of disorders, the prophylactic treatment is optimal duringthe inactive periods such that the amounts of inhibitoryneurotransmitters in the brain can remain at a higher enough level tomitigate or abort an acute attack of the disorder.

In these embodiments, the prophlatic treatment may comprise multipledoses/day timed for periods of inactivity of the locus correleus. In oneembodiment, a treatment according to the present invention comprises oneor more doses administered 2-3 times per day or 2-3 “treatment sessions”per day. The treatment sessions preferably occur during the lateafternoon or late evening, in the middle of the night and again in themorning when the patient wakes up. In an exemplary embodiment, eachtreatment session comprises 1-4 doses, preferably 2-3 doses, with eachdose lasting for about 90 seconds to about three minutes.

For other disorders, the intervals between treatment sessions may be themost important as applicant has determined that stimulation of the vagusnerve can have a prolonged effect on the inhibitor neurotransmitterslevels in the brain, e.g., at least one hour, up to 3 hours andsometimes up to 8 hours. In one embodiment, a treatment according to thepresent invention comprises one or more doses (i.e., treatment sessions)administered at intervals during a 24 hour period. In a preferredembodiment, there are 1-5 such treatment sessions, preferably 2-4treatment sessions. Each treatment session preferably comprises 1-3doses, each lasting between about 60 seconds to about three minutes,preferably about 90 seconds to about 150 seconds, more preferably about2 minutes.

For an acute treatment, such as treatment of acute stroke, the therapyaccording to the present invention may comprise one or more embodiments:(1) 1 dose at the onset of symptoms; (2) 1 dose at the onset ofsymptoms, followed by another dose at 5-15 min; or (3) 1 dose every 15minutes to 1 hour at the onset of symptoms until the acute attack hasbeen mitigated or aborted. In these embodiments, each dose preferablylast between about 60 seconds to about three minutes, preferably about90 seconds to about 150 seconds, more preferably about 2 minutes.

For long term treatment of an acute insult such as one that occursduring the rehabilitation of a stroke patient, the therapy may consistof: (1) 3 treatments/day; (2) 2 treatments, either consecutively orseparated by 5 min, 3×/day; (3) 3 treatments, either consecutively orseparated by 5 min, 2×/day; (4) 2 or 3 treatments, either consecutivelyor separated by 5 min, up to 10×/day; or (5) 1, 2 or 3 treatments,either consecutively or separated by 5 min, every 15, 30, 60 or 120 min.

For all of the treatments listed above, one may alternate treatmentbetween left and right sides, or in the case of stroke or migraine thatoccur in particular brain hemispheres, one may treat ipsilateral orcontralateral to the stroke-hemisphere or headache side, respectively.Or for a single treatment, one may treat one minute on one side followedby one minute on the opposite side. Variations of these treatmentparadigms may be chosen on a patient-by-patient basis. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's condition changes. In preferred embodiments, the disclosedmethods and devices do not produce clinically significant side effects,such as agitation or anxiety, or changes in heart rate or bloodpressure.

The prophylactic treatments may be most effective when the patient is ina prodromal, high-risk bistable state. In that state, the patient issimultaneously able to remain normal or exhibit symptoms, and theselection between normal and symptomatic states depends on theamplification of fluctuations by physiological feedback networks. Forexample, a thrombus may exist in either a gel or fluid phase, with thefeedback amplification of fluctuations driving the change of phaseand/or the volume of the gel phase. Thus, a thrombus may form or not,depending on the nonlinear dynamics exhibited by the network of enzymesinvolved in clot formation, as influenced by blood flow and inflammationthat may be modulated by vagus nerve stimulation [PANTELEEV M A,Balandina A N, Lipets E N, Ovanesov M V, Ataullakhanov F I.Task-oriented modular decomposition of biological networks: triggermechanism in blood coagulation. Biophys J 98(9, 2010):1751-1761; AlexeyM SHIBEKO, Ekaterina S Lobanova, Mikhail A Panteleev and Fazoil IAtaullakhanov. Blood flow controls coagulation onset via the positivefeedback of factor VII activation by factor Xa. BMC Syst Biol 2010; 4(2010):5, pp. 1-12]. Consequently, the mechanisms of vagus nervestimulation treatment during prophylaxis for a stroke are generallydifferent than what occurs during an acute treatment, when thestimulation inhibits excitatory neurotransmission that follows the onsetof ischemia that is already caused by the thrombus. Nevertheless, theprophylactic treatment may also inhibit excitatory neurotransmission soas to limit the excitation that would eventually occur upon formation ofa thrombus, and the acute treatment may prevent the formation of anotherthrombus.

The circuits involved in such inhibition are illustrated in FIG. 1A.Excitatory nerves within the dorsal vagal complex generally useglutamate as their neurotransmitter. To inhibit neurotransmission withinthe dorsal vagal complex, the present invention makes use of thebidirectional connections that the nucleus of the solitary tract (NTS)has with structures that produce inhibitory neurotransmitters, or itmakes use of connections that the NTS has with the hypothalamus, whichin turn projects.

The general stimulation schedules described above, or an individualizedprotocol fashioned for each patient, are designed or justified usingconcepts that are analogous to the selection of drug treatmentprotocols. For drugs, pharmacological dose-response experiments measurethe cumulative effect of a bolus of the drug on the physiologicalparameter that is to be controlled as a function of time (e.g., bloodpressure). After administration of the drug, the effective concentrationof the drug decreases, typically with an exponentially decayinghalf-life, but sometimes with a complex decay pattern, and the effect ofthe drug on the physiological parameter also eventually decreases. Thesituation is similar with vagus nerve stimulation. The effectiveness ofvagus nerve stimulation on a physiological parameter may also beconsidered quantitatively (e.g., EEG-derived index of cerebral ischemia,see: FERREE T C, Hwa R C. Electrophysiological measures of acutecerebral ischaemia. Phys Med Biol 50(17, 2005):3927-3939). Theeffectiveness is a function of the stimulation voltage, the duration ofthe stimulation, and if stimulation has ceased, the time since cessationof the last stimulation. Accordingly, the numerical value of an“Accumulated Vagus Nerve Stimulation” with a particular waveform may bedenoted as S(t) and may for present purposes be represented as one thatincreases at a rate proportional to the stimulation voltage V and decayswith a time constant TAU_(P), such that after prolonged stimulation, theaccumulated stimulation effectiveness will saturate at a value equal tothe product of V and TAU_(P). Thus, if T_(p) is the duration of astimulus pulse, then for time t<T_(P),S(t)=V□_(P [)1−exp(−t/TAU_(P))]+S₀ exp(−t/TAU_(P)). For t>T_(P),S(t)=S(T_(P)) exp (−[t−T_(P)]/TAU_(P)), where the time t is measuredfrom the start of a pulse, S₀ is the value of S when t=0, and thestimulation voltage V may be expressed in units of the volts needed tofirst elicit a response on the part of the patient. Because each patientmay have a different value of TAU_(P), the stimulus protocol needed tomaintain the physiological value above or below a certain pre-determinedvalue may likewise vary from patient to patient. If the decay of thenerve stimulation effect is complex, a model more complicated thansimple exponential decay should be used, analogous to more complexmodels used in pharmacokinetics and pharmacodymanics.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a additional sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect.

For example, the hypothalamus is well known to be responsive to thepresence of bright light, so exposing the patient to bright light thatis fluctuating with the same stimulation frequency as the vagus nerve(or a multiple of that frequency) may be performed in an attempt toenhance the role of the hypothalamus in producing the desiredtherapeutic effect. Such paired stimulation does not necessarily relyupon neuronal plasticity and is in that sense different from otherreports of paired stimulation [Navzer D. ENGINEER, Jonathan R. Riley,Jonathan D. Seale, Will A. Vrana, Jai A. Shetake, Sindhu P. Sudanagunta,Michael S. Borland and Michael P. Kilgard. Reversing pathological neuralactivity using targeted plasticity. Nature 470(7332, 2011):101-104;PORTER B A, Khodaparast N, Fayyaz T, Cheung R J, Ahmed S S, Vrana W A,Rennaker R L 2nd, Kilgard M P. Repeatedly pairing vagus nervestimulation with a movement reorganizes primary motor cortex. CerebCortex 22(10, 2012):2365-2374].

Selection of stimulation parameters to preferentially stimulateparticular regions of the brain may be done empirically, wherein a setof stimulation parameters are chosen, and the responsive region of thebrain is measured using fMRI or a related imaging method [CHAE J H,Nahas Z, Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S.A review of functional neuroimaging studies of vagus nerve stimulation(VNS). J Psychiatr Res. 37(6, 2003):443-455; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2, 2006):179-84]. Thus, by performing the imaging with differentsets of stimulation parameters, a database may be constructed, such thatthe inverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

Stimulation waveforms may also be constructed by superimposing or mixingthe burst waveform shown in FIG. 2, in which each component of themixture may have a different period T, effectively mixing differentburst-per-second waveforms. The relative amplitude of each component ofthe mixture may be chosen to have a weight according to correlations indifferent bands in an EEG for a particular resting state network. Thus,MANTINI et al performed simultaneous fMRI and EEG measurements and foundthat each resting state network has a particular EEG signature [see FIG.3 in: MANTINI D, Perrucci M G, Del Gratta C, Romani G L, Corbetta M.Electrophysiological signatures of resting state networks in the humanbrain. Proc Natl Acad Sci USA 104(32, 2007):13170-13175]. They reportedrelative correlations in each of the following bands, for each restingstate network that was measured: delta (1-4 Hz), theta (4-8 Hz), alpha(8-13 Hz), beta (13-30 Hz), and gamma (30-50 Hz) rhythms. Forrecently-identified resting state networks, measurement of thecorresponding signature EEG networks will have to be performed.

According to the present embodiment of the invention, multiple signalsshown in FIG. 2 are constructed, with periods T that correspond to alocation near the midpoint of each of the EEG bands (e.g., using theMINATI data, T equals approximately 0.4 sec, 0.1667 sec, 0.095 sec,0.0465 sec, and 0.025 sec, respectively). A more comprehensive mixturecould also be made by mixing more than one signal for each band. Thesesignals are then mixed, with relative amplitudes corresponding to theweights measured for any particular resting state network, and themixture is used to stimulate the vagus nerve of the patient. Phasesbetween the mixed signals are adjusted to optimize the fMRI signal forthe resting state network that is being stimulated, thereby producingentrainment with the resting state network. Stimulation of a network mayactivate or deactivate a network, depending on the detailedconfiguration of adrenergic receptors within the network and their rolesin enhancing or depressing neural activity within the network, as wellas subsequent network-to-network interactions. It is understood thatvariations of this method may be used when different combined fMRI-EEGprocedures are employed and where the same resting state may havedifferent EEG signatures, depending on the circumstances [WU C W, Gu H,Lu H, Stein E A, Chen J H, Yang Y. Frequency specificity of functionalconnectivity in brain networks. Neuroimage 42(3, 2008):1047-1055; LAUFSH. Endogenous brain oscillations and related networks detected bysurface EEG-combined fMRI. Hum Brain Mapp 29(7, 2008):762-769; MUSSO F,Brinkmeyer J, Mobascher A, Warbrick T, Winterer G. Spontaneous brainactivity and EEG microstates. A novel EEG/fMRI analysis approach toexplore resting-state networks. Neuroimage 52(4, 2010):1149-1161;ESPOSITO F, Aragri A, Piccoli T, Tedeschi G, Goebel R, Di Salle F.Distributed analysis of simultaneous EEG-fMRI time-series: modeling andinterpretation issues. Magn Reson Imaging 27(8, 2009):1120-1130; FREYERF, Becker R, Anami K, Curio G, Villringer A, Ritter P.Ultrahigh-frequency EEG during fMRI: pushing the limits ofimaging-artifact correction. Neuroimage 48(1, 2009):94-108]. Once thenetwork is entrained, one may also attempt to change the signature EEGpattern of a network, by slowly changing the frequency content of thestimulation & EEG pattern of the network to which the stimulator isinitially entrained. An objective in this case would be to modify thefrequency content of the resting state signature EEG.

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of skin pain or muscle twitches.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted. Alternatively, the selection ofparameter values may involve tuning as understood in control theory, andas described below. It is understood that parameters may also be variedrandomly in order to simulate normal physiological variability, therebypossibly inducing a beneficial response in the patient [Buchman T G.Nonlinear dynamics, complex systems, and the pathobiology of criticalillness. Curr Opin Crit Care 10(5, 2004):378-82].

Use of Control Theory Methods to Improve Treatment of IndividualPatients

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve; to avoid potentially dangerous situationssuch as excessive heart rate; and to maintain measured EEG bands (e.g.,delta, theta, alpha, beta) within predetermined ranges, in attempt topreferentially activate particular resting state networks. Thus, withthese methods, the parameters of the vagus nerve stimulation may bechanged automatically, depending on physiological measurements that aremade, in attempt to maintain the values of the physiological signalswithin predetermined ranges.

Measurement of the patient's EEG is preferably performed as part of onedisclosed method for selecting the parameters of vagus nervestimulation, as described in the previous section. The EEG also providesdynamic physiological data concerning the onset and course of an acutestroke [JORDAN K G. Emergency EEG and continuous EEG monitoring in acuteischemic stroke. J Clin Neurophysiol 21(5, 2004):341-352; FERREE T C,Hwa R C. Electrophysiological measures of acute cerebral ischaemia. PhysMed Biol 50(17, 2005):3927-3939].

It is understood that the effects of vagus nerve stimulation on surfaceEEG waveforms may be difficult to detect [Michael BEWERNITZ, GeorgesGhacibeh, Onur Seref, Panos M. Pardalos, Chang-Chia Liu, and BasimUthman. Quantification of the impact of vagus nerve stimulationparameters on electroencephalographic measures. AIP Conf. Proc. DATAMINING, SYSTEMS ANALYSIS AND OPTIMIZATION IN BIOMEDICINE; Nov. 5, 2007,Volume 953, pp. 206-219], but they may exist nevertheless [KOO B. EEGchanges with vagus nerve stimulation. J Clin Neurophysiol. 18(5,2001):434-41; KUBA R, Guzaninová M, Brázdil M, Novák Z, Chrastina J,Rektor I. Effect of vagal nerve stimulation on interictal epileptiformdischarges: a scalp EEG study. Epilepsia. 43(10, 2002):1181-8; RIZZO P,Beelke M, De Carli F, Canovaro P, Nobili L, Robert A, Formaro P,Tanganelli P, Regesta G, Ferrillo F. Modifications of sleep EEG inducedby chronic vagus nerve stimulation in patients affected by refractoryepilepsy. Clin Neurophysiol. 115(3, 2004):658-64].

When stimulating the vagus nerve, motion variability may often beattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 7).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 8 is a control theory representation of the disclosed vagus nervestimulation methods. As shown there, the patient, or the relevantphysiological component of the patient, is considered to be the “System”that is to be controlled. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound. If the “System” is defined to be only aparticular physiological component of the patient, the “Environment” mayalso be considered to include physiological systems of the patient thatare not included in the “System”. Thus, if some physiological componentcan influence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 2. Feedback in the schema shown in FIG. 8 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A. M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst 34(2010):195-212]. In the present application, the features would includeEEG bands (e.g., delta, theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. Respiratory phase may also be inferred frommovement of the sternocleidomastoid muscle that also causes movement ofthe vagus nerve stimulator during breathing, measured usingaccelerometers attached to the vagus nerve stimulator, as describedbelow. After digitizing such signals, the phase of respiration may bedetermined using software such as “puka”, which is part ofPhysioToolkit, a large published library of open source software anduser manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral L A N, Glass L, HausdorffJ M, Ivanov P Ch, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a NewResearch Resource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the magnetic stimulator coils or electrodes,depending on the phase of the patient's respiration. In patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO, a system is also described for keeping the heart rate withinsafe limits. When the heart rate is too high, that system stimulates apatient's vagus nerve, and when the heart rate is too low, that systemtries to achieve stabilization of the heart rate by stimulating theheart itself, rather than use different parameters to stimulate thevagus nerve. In that disclosure, vagal stimulation uses an electrode,which is described as either a surface electrode applied to the bodysurface or an electrode introduced to the vicinity of the vagus nervevia a hypodermic needle. That disclosure is unrelated to stroke ortransient ischemic attack problems that are addressed here, but it doesconsider stimulation during particular phases of the respiratory cycle,for the following reason. Because the vagus nerve is near the phrenicnerve, Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants have not experienced this problem, so the problem may be oneof a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.

The present invention also discloses stimulation of the vagus nerve as afunction of respiratory phase, but the rationale for such stimulation isdifferent from Yoshihoto's method.

In some embodiments of the invention, overheating of the magneticstimulator coil may also be minimized by optionally restricting themagnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, so as toachieve and maintain the heart rate within safe or desired limits. Inthat case, the parameters of the stimulation are individually raised orlowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention, and as described above, the control unit 330 extractsthe systolic, diastolic, and mean arterial blood pressure from the bloodpressure waveform. The control unit 330 will then control the impulsegenerator 310 in such a way as to temporally modulate nerve stimulationby the magnetic stimulator coil or electrodes, in such a way as toachieve and maintain the blood pressure within predetermined safe ordesired limits, by the same method that was indicated above for theheart rate. Thus, even if one does not intend to treat problemsassociated with stroke, embodiments of the invention described above maybe used to achieve and maintain the heart rate and blood pressure withindesired ranges.

Let the measured output variables of the system in FIG. 8 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). The objective is for a controllerto select the input u_(j) in such a way that the output variables (or asubset of them) closely follows the reference signals r_(i), i.e., thecontrol error e_(i)=r_(i)−y_(i) is small, even if there is environmentalinput or noise to the system. Consider the error functione_(i)=r_(i)−y_(i) to be the sensed physiological input to the controllerin FIG. 8 (i.e., the reference signals are integral to the controller,which subtracts the measured system values from them to construct thecontrol error signal). The controller will also receive a set ofmeasured environmental signals v_(k) (k=1 to R), which also act upon thesystem as shown in FIG. 8.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2D and 2E. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1, 1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed or helped to perform neckmovements, breathe deeply so as to contract the sternocleidomastoidmuscle, and generally simulate possible motion that may accompanyprolonged stimulation with the stimulator. This would include possibleslippage or movement of the stimulator relative to an initial positionon the patient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, ornell University, 2007; Bartosz SAWICKI, Robert Szmur

o, Przemys

aw P

onecki, Jacek Starzyński, Stanis

aw Wincenciak, Andrzej Rysz. Mathematical Modelling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, IOS Press, 2008].Thus, in order to compensate for movement, the controller may increaseor decrease the amplitude of the output from the stimulator (u) inproportion to the inferred deviation of the amplitude of the electricfield in the vicinity of the vagus nerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the formdy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(i)}), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form:

${u(t)} = {{K_{p}{e(t)}} + {K_{i}{\int_{0}^{t}{{e(\tau)}{\tau}}}} + {K_{d}\frac{e}{t}}}$

where the parameters for the controller are the proportional gain(K_(p)), the integral gain (K_(i)) and the derivative gain (K_(d)). Thistype of controller, which forms a controlling input signal with feedbackusing the error e=r−y, is known as a PID controller(proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [LI, Y., Ang, K. H. and Chong, G. C. Y. Patents, software andhardware for PID control: an overview and analysis of the current art.IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl Johan Astrom &Richard M. Murray. Feedback Systems: An Introduction for Scientists andEngineers. Princeton N.J.: Princeton University Press, 2008; FinnHAUGEN. Tuning of PID controllers (Chapter 10) In: Basic Dynamics andControl. 2009. ISBN 978-82-91748-13-9. TechTeach, Enggravhøgda 45,N-3711 Skien, Norway. http://techteach.no., pp. 129-155; Dingyu XUE,YangQuan Chen, Derek P. Atherton. PID controller design (Chapter 6), In:Linear Feedback Control Analysis and Design with MATLAB. Society forIndustrial and Applied Mathematics (SIAM). 3600 Market Street, 6thFloor, Philadelphia, Pa. (2007), pp. 183-235; Jan JANTZEN, Tuning OfFuzzy PID Controllers, Technical University of Denmark, report 98-H 871,Sep. 30, 1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. To use such a controller, forexample, in an attempt to maintain the EEG gamma band at a particularlevel relative to the alpha band, one could set the integral andderivative gains to zero, increase the proportional gain (amplitude ofthe stimulation) until the relative gamma band level starts tooscillate, and then measure the period of oscillation. The PID wouldthen be set to its tuned parameter values.

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 8 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

The controller shown in FIG. 8 may also make use of feed-forward methods[Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In:Techniques of Model-Based Control. Upper Saddle River, N.J.: PrenticeHall PTR, 2002. pp, 221-240]. Thus, the controller in FIG. 8 may be atype of predictive controller, methods for which have been developed inother contexts as well, such as when a model of the system is used tocalculate future outputs of the system, with the objective of choosingamong possible inputs so as to optimize a criterion that is based onfuture values of the system's output variables.

Performance of system control can be improved by combining the feedbackclosed-loop control of a PID controller with feed-forward control,wherein knowledge about the system's future behavior can be fed forwardand combined with the PID output to improve the overall systemperformance. For example, if the sensed environmental input in FIG. 8 issuch the environmental input to the system will have a deleteriouseffect on the system after a delay, the controller may use thisinformation to provide anticipatory control input to the system, so asto avert or mitigate the deleterious effects that would have been sensedonly after-the-fact with a feedback-only controller.

A mathematical model of the system is needed in order to perform thepredictions of system behavior, e.g., make predictions concerning thepatient's future status regarding a stroke or transient ischemic attack.Models that are completely based upon physical first principles(white-box) are rare, especially in the case of physiological systems.Instead, most models that make use of prior structural and mechanisticunderstanding of the system are so-called grey-box models. If themechanisms of the systems are not sufficiently understood in order toconstruct a white or grey box model, a black-box model may be usedinstead. Such black box models comprise autoregressive models [TimBOLLERSLEV. Generalized autoregressive condiditional heteroskedasticity.Journal of Econometrics 31 (1986):307-327], or those that make use ofprincipal components [James H. STOCK, Mark W. Watson. Forecasting withMany Predictors, In: Handbook of Economic Forecasting. Volume 1, G.Elliott, C. W. J. Granger and A. Timmermann, eds (2006) Amsterdam:Elsevier B. V, pp 515-554], Kalman filters [Eric A. WAN and Rudolph vander Merwe. The unscented Kalman filter for nonlinear estimation, In:Proceedings of Symposium 2000 on Adaptive Systems for Signal Processing,Communication and Control (AS-SPCC), IEEE, Lake Louise, Alberta, Canada,October, 2000, pp 153-158], wavelet transforms [O. RENAUD, J.-L. Stark,F. Murtagh. Wavelet-based forecasting of short and long memory timeseries. Signal Processing 48 (1996):51-65], hidden Markov models [SamROWEIS and Zoubin Ghahramani. A Unifying Review of Linear GaussianModels. Neural Computation 11(2, 1999): 305-345], or artificial neuralnetworks [Guoquiang ZHANG, B. Eddy Patuwo, Michael Y. Hu. Forecastingwith artificial neural networks: the state of the art. InternationalJournal of Forecasting 14 (1998): 35-62].

For the present invention, if a black-box model must be used, thepreferred model will be one that makes use of support vector machines. Asupport vector machine (SVM) is an algorithmic approach to the problemof classification within the larger context of supervised learning. Anumber of classification problems whose solutions in the past have beensolved by multi-layer back-propagation neural networks, or morecomplicated methods, have been found to be more easily solvable by SVMs[Christopher J. C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2 (1998),121-167; J. A. K. SUYKENS, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;SAPANKEVYCH, N. and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine 4(2,2009): 24-38; PRESS, W H; Teukolsky, S A; Vetterling, W T; Flannery, B P(2007). Section 16.5. Support Vector Machines. In: Numerical Recipes:The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

Consider now the problem of predicting and possibly averting a stroke ortransient ischemic attack. The example assumes that vagus nervestimulation can be applied as described above, but the stimulation isapplied only when the invention's feedforward system predicts that astroke or transient ischemic attack is imminent. Candidates for thedisclosed forecasting methods include individuals who have had a recenttransient ischemic attack and are likely to suffer a stroke in the nextfew days [JOHNSTON S C, Rothwell P M, Nguyen-Huynh M N, Giles M F,Elkins J S, Bernstein A L, Sidney S. Validation and refinement of scoresto predict very early stroke risk after transient ischaemic attack.Lancet 369(9558, 2007):283-292].

A training set of physiological data will have been acquired thatincludes whether or not a stroke or transient ischemic attack is inprogress. Thus, the binary classification of the patient's state iswhether or not a stroke or transient ischemic attack is in progress, andthe data used to make the classification consist of acquiredphysiological data. The training data would preferably be acquired froma single individual, but as a practical matter the training set of datawill ordinarily be obtained from a group of individuals who volunteerfor ambulatory or hospital physiological monitoring. In general, themore physiological data that are acquired, the better the forecast willbe.

Prediction that a stroke or TIA is imminent may be based upon the likelyformation of a thrombosis or arterial embolism. In that regard, thereexists an ambulatory monitoring device that will monitor for cerebralemboli [MacKINNON A D, Aaslid R, Markus H S. Long-term ambulatorymonitoring for cerebral emboli using transcranial Doppler ultrasound.Stroke 35(1, 2004):73-8]. It measures the passage of emboli, typicallyat the middle cerebral artery, using a transcranial Doppler signal.Whereas some cerebral emboli produce symptoms of a stroke, other embolido not produce symptoms and may not be recognized by the patient.Therefore, in one embodiment of the invention, the detection of anembolus with the device mentioned above is used as input for theforecasting of a TIA or stroke, but the appearance of the embolus in andof itself does not necessarily trigger the forecast of an imminent TIAor stroke. Additional physiological variables are used to make theforecast.

Preferably, the additional physiological variables should include EEGand its derived features, heart rate (electrocardiogram leads), bloodpressure (noninvasive tonometer), respiration (e.g., abdominal andthoracic plethysmography), and motion (accelerometer). For themonitoring of drug and medications, systemic metabolism, and changes incoagulation, body chemistry may also be measure noninvasively usingtransdermal reverse iontophoresis [Leboulanger B, Guy R H,Delgado-Charro M B. Reverse iontophoresis for non-invasive transdermalmonitoring. Physiol Meas 25(3, 2004):R35-50]. Preferably, the ambulatorynoninvasive measurements would also include skin impedance(electrodermal leads), carbon dioxide (capnometry with nasual cannula),vocalization (microphones), light (light sensor), external and fingertemperature (thermometers), etc., as well as parameters of thestimulator device, all evaluated at A time units prior to the time atwhich binary “stroke or transient ischemic attack in progress” (yes/no)data are acquired. Many values of delta may be considered, from secondsto minutes to hours. In general, as the value of delta increases, thecalculated uncertainty of the forecast will also increase. The onset ofthe stroke or transient ischemic attack may be inferred from the data(e.g., EEG data) and/or from a patient activated event marker upon theappearance of symptoms such as sudden weakness or numbness, and dimmingor loss of vision.

The selection of ambulatory noninvasive measurements may be motivated byphysiological considerations. For example, the ECG may automaticallymonitor the presence (or forecast) of atrial fibrillation, ambulatoryblood pressure monitors for the presence of acute increases in bloodpressure, and body temperature thermometers monitors the presence ofinfection and inflammation. The status of the autonomic nervous systemis likewise monitored through heart rate variability (via the ECG) andskin impedance. The EEG may also provide evidence of the onset andprogression of ischemia [FERREE T C, Hwa R C. Electrophysiologicalmeasures of acute cerebral ischaemia. Phys Med Biol 50(17,2005):3927-3939]. However, because the detailed physiological mechanismsof ischemic events are not fully understood, and a black box model isbeing used to make the forecast, physiological variables with anuncertain relevance to ischemia may also be monitored.

For a patient who is not experiencing a stroke or transient ischemicattack, the SVM is trained to forecast the imminence of a stroke ortransient ischemic attack, Δ time units into the future, and thetraining set includes the above-mentioned physiological signals. The SVMis also trained to forecast the termination of a transient ischemicattack, Δ time units into the future, and the training set includes thetime-course of features extracted from the above-mentioned physiologicalsignals. After training the SVM, it is implemented as part of thecontroller. The controller may apply the vagus nerve stimulation as aprophylactic whenever there is a forecast of imminent stroke ortransient ischemic attack. The controller may also be programmed to turnoff the vagaus nerve stimulation when it forecasts or detects thetermination of a transient ischemic attack. It is understood that in anyevent, the patient should treat any in-progress stroke or transientischemic attack as a medical emergency and seek immediate emergencymedical attention, notwithstanding the use of vagus nerve stimulation asa prophylactic. If the stroke or transient ischemic attack is onlyforecasted, the patient should immediately seek transportation to thewaiting room of the nearest acute stroke treatment center or emergencyroom and wait at that location to see whether the predicted stroke ortransient ischemic attack happens, notwithstanding the use of vagusnerve stimulation as a prophylactic that may have prevented the event.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A device for modulating one or more nerves within a body of a patientcomprising: a handheld device comprising an enclosure with an interiorand an electrically conductive interface configured for contact with anouter skin surface of a patient; a source of energy housed within theinterior of the enclosure; a signal generator housed within theenclosure and coupled to the source of energy, the signal generatorbeing configured to apply an electrical impulse through the electricallyconductive interface of the enclosure transcutaneously through an outerskin surface of the patient to a nerve at a target region below theouter skin surface; and a filter housed within the enclosure andelectrically coupling the signal generator with the electricallyconductive interface, wherein the filter is configured to filter outhigh frequency components from the electrical impulse.
 2. The device ofclaim 1 wherein the filter comprises an electrically conductive fluidhoused within the enclosure between the signal generator and theelectrically conductive interface.
 3. The device of claim 2 wherein theelectrically conductive fluid comprises a conductive gel.
 4. The deviceof claim 1 wherein the filter comprises a low-pass filter electricallycoupled between the signal generator and the electrically conductiveinterface.
 5. The device of claim 1 wherein the electrically conductiveinterface comprises first and second electrically conductive membranesthat function as electrodes.
 6. The device of claim 1 wherein theelectrical impulse is sufficient to modulate a nerve within the targetregion and insufficient to substantially modulate nerve(s) in thevicinity of the outer skin surface.
 7. The device of claim 1 wherein thesource of energy is configured to generate an electrical fieldcomprising bursts of sinusoidal pulses with silent inter-burst periodssuch that each burst has a frequency of about 5 to about 100 Hz.
 8. Thedevice of 7 wherein the sinusoidal pulses have a frequency of about 1 toabout 20 KHz.
 9. The device of claim 7 wherein the sinusoidal pulseshave a frequency of about 1 to about 10 KHz.
 10. The device of claim 7wherein the sinusoidal pulses have a frequency of about 5 KHz.
 11. Thedevice of claim 1 wherein the electrically conductive interfacecomprises stainless steel.
 12. The device of claim 6 wherein the burstseach have a frequency of about 10 to about 35 Hz.
 13. A device formodulating one or more nerves within a body of a patient comprising: ahandheld device comprising an enclosure with an interior and one or moreelectrodes configured for contact with an outer skin surface of apatient; a source of energy housed within the interior of the enclosure;a signal generator housed within the enclosure and coupled to the sourceof energy, the signal generator being configured to apply an electricalimpulse through the electrodes transcutaneously through an outer skinsurface of the patient to a nerve at a target region below the outerskin surface; and an electrically conductive fluid housed within theenclosure and electrically coupling the signal generator with theelectrodes.
 14. The device of claim 13 wherein the electricallyconductive fluid comprises a conductive gel.
 15. The device of claim 13wherein the electrical impulse is sufficient to modulate a nerve withinthe target region and insufficient to substantially modulate nerve(s) inthe vicinity of the outer skin surface.
 16. The device of claim 13wherein the source of energy is configured to generate an electricalfield comprising bursts of sinusoidal pulses with silent inter-burstperiods such that each burst has a frequency of about 5 to about 100 Hz.17. The device of 16 wherein the sinusoidal pulses have a frequency ofabout 1 to about 20 KHz.
 18. The device of claim 16 wherein thesinusoidal pulses have a frequency of about 1 to about 10 KHz.
 19. Thedevice of claim 16 wherein the sinusoidal pulses have a frequency ofabout 5 KHz.
 20. The device of claim 1 wherein the electricallyconductive interface comprises stainless steel.
 21. The device of claim16 wherein the bursts each have a frequency of about 10 to about 35 Hz.